Massage Blends for Stress Relief

IMPACT OF ESSENTIAL OILS ON MOOD

As our lives become faster in a world that is increasingly demanding and, for some, seemingly threatening, depression and anxiety is something many of us might experience at some point in our life. While depression and anxiety are nothing new, most of us can recognize the growing profile and prevalence of this psychological phenomenon in our modern world.

Whether we face a stressful period of our life, find ourselves unable to manage the general buildup of stress (whether from balancing work, family or relationships), or must confront a more severe and enduring emotional battle, most of us can relate to a moment in time when we find ourselves unable to cope with our day to day lives. But life is meant to be joyful, not filled with stress.

Today, we live in what many theorists refer to as “The Medicated State”, where psychiatry and neuropsychology (viewing depression and anxiety through the perspective of physical events in the brain that can be chemically manipulated) have increasingly ruled the day. This has been born with an emphasis on the evolution of science and technology on developing pharmaceutical drugs. It has become popular because of economic factors, seen as a practical alternative to other forms of psychology that are costly in both time and money (such as therapy, which is economically unviable for many people).

There are many natural ways to combat stress and actively control mood swings. There is no single solution, and even modern pharmaceuticals used in treating clinical depression and anxiety disorders must concede an element of subjectivity and individualism of psychological make-up and even the most popular psychoactive drugs have different effects on people and can work for some and not others. No one situation is the same, nor the mind that is affected by it. For many who have turned to natural solutions to combat mild stress and unhappiness, aromatherapy has provided a valuable tool, alongside exercise and a healthy diet.

Many aromatherapy treatments have long been heralded as a natural way of inducing states of calm. If you find yourself suffering extreme states of anxiety and depression, it is important to seek psychological or medical advice. But there are various ways that secrets of aromatherapists can be useful for mild and every-day stress and low mood; and even in conjunction with other treatments, it can provide one more method of finding a solution that works for you. Firstly, the oils may directly affect mood levels.

For feelings of unhappiness or low mood, it is a good idea to choose those which have been attributed to an uplifting effect, which may alter both mood and energy levels. These include:

  • Bergamot
  • Cypress
  • Lemongrass
  • Rosemary
  • Sage

ESSENTIAL OILS FOR STRESS RELIEF

Those who suffer from stress will battle increased neural activity, as our problems literally keep us awake. This can ironically lessen our ability to deal with the problems causing this stress, as we miss out on the restorative powers of deep sleep and suffer the physical and psychological consequences (increasing the feeling of being “burnt out”, or physically and emotionally pushed beyond one’s limits).

Those who are experiencing a period of unhappiness and low mood may also have interrupted sleep patterns because of serotonin – the natural brain chemical connected to our mood and feelings of well-being – plays a role in the regulation of sleep. When we are feeling low or unhappy, our serotonin levels have dropped; this shortage can, in turn, cause erratic sleep or insomnia.

Many aromatherapy treatments have long been heralded as a natural way of inducing states of calm and (therefore) sleep; so, whilst these oils do not directly address the chemical levels in the brain (as do anti-depressants and psycho-active medication), they can help other elements of our life that do (such as sleep).

There’s nothing more powerful to help us deal with our stress than to spend time relaxing and gathering ourselves in a state of calm with which to approach our busy lives. Oils for this include:

  • Chamomile
  • Geranium
  • Jasmine
  • Lavender
  • Marjoram
  • Neroli
  • Patchouli
  • Rose
  • Sandalwood
  • Ylang Ylang

Beyond this, it is important to remember that smell is also a phenomenon that works emotionally on the basis of personal association. While these listed oils are thought to have properties that work on a more direct physical level, never underestimate the power of scent in terms of the connections we give them. A past client of mine once used raspberry oil because it reminded her of the raspberry bushes that lined her front porch where she would watch the sunset as a child. This subconscious association facilitated a powerful regression that gave her feelings of safety and well-being during trying times. Even though raspberry oil may not classically be seen as having any emotionally effective properties, her mind had created a powerful association that was entirely her own, and entirely effective. What’s more is that she had arrived at this realization after exploring her attraction to anything raspberry without her understanding the origins. Like many people, she had never given the origins of her personal penchants much thought. But when I asked her why she found herself drawn to the scent of raspberry whenever she was down (suggesting an obvious unconscious mechanism to create a happier space) she remembered her fond memories on the front porch of her parents’ farm. She soon purchased some raspberry essential oil, and to this day, I imagine uses it to comfort her whenever she feels overwhelmed by the day-to-day trials of her life.

So, never underestimate the power of smell! Referred to as Olfactory Psychology, this is an area still very much being explored by modern science, and it is generally conceded that the realm of scent is indeed a powerful but complicated world. Whilst depression and anxiety can – at the extreme end – be a largely physical phenomenon, for most of us, the stress and unhappiness we encounter and experience is still predominantly a problem that is psychodynamic (that is, connected to events in our lives and the context in which we deal with them), and each has a complex relationship between their psychological make-up, what has happened in their lives, what is currently happening and their ability to react and deal with the things that can cause us stress or bring our mood down. The scent and, most importantly, our associations with scent, plays a vital role in this, alongside a myriad of other components. It is a powerful and unique concept to remember when approaching the world of Aromatherapy – a world that may run even deeper than many think.

IN ESSENCE…

    • Aromatherapy has provided a natural solution to combat the consequences of the complex relationship between our stress and our psychological make-up.
    • Scent and, most importantly, our associations with scent, play a vital role in dealing with the things that can bring our mood down.
    • For feelings of stress and grief, it is a good idea to choose essential oils that are known to have an uplifting effect.
    • There’s nothing more powerful to help us deal with our stress than to spend time relaxing and gathering ourselves in a state of calm, for which there are ideal essential oils.
  • Aromatherapy can be a valuable tool for stress relief alongside exercise and a healthy diet.

STRESS RELIEVING BLEND

The following combination of essential oils helps to reduce stress and tension and their associated symptoms:

INGREDIENTS MEASURE
Carrier Oil
(Sweet Almond Oil, Avocado Oil, or Grape Seed Oil recommended)
7 t.
Bergamot Essential Oil 5 drops
Mandarin Essential Oil 4 drops
Lavender Essential Oil 4 drops
Lemongrass Essential Oil 3 drops

INSTRUCTIONS:

  1. Mix the essential oils.
  2. Dilute by adding the carrier oil.
  3. Massage onto chest for comforting and penetrating warmth.

 


 

    • Carrier Oil (Sweet Almond Oil, Avocado Oil, or Grape Seed Oil recommended): Avocado carrier oil is an odorless healing oil that is silky to the touch and easily absorbed by the skin. Its anti-wrinkle and regenerative properties prevent the early onset of visible signs of aging by keeping the skin hydrated, nourished, elastic, and soft.

 

    • Bergamot Essential Oil: This energizing oil is known to boost blood circulation and to reduce nervous tension, stress, and anxiety, which in turn replaces negative mental states with feelings of joy, refreshment, and vigor. The relief of heavy emotional stressors such as sadness may lead to reduced blood pressure, relaxation, and better regulation of the sleep hormones serotonin and dopamine, which may lead to better sleep.

 

    • Mandarin Essential Oil: This sedative oil relaxes the nerves and promotes feelings of calm, eliminating stress and anxiety.

 

    • Lavender Essential Oil: This calming oil is a popular choice for those looking to relieve both emotional and physical stress ranging from sadness to headaches. Its soothing scent diminishes feelings of restlessness and exhaustion.

 

  • Lemongrass Essential Oil: This sedative oil is commonly used to relieve anxiety, irritability, and sleeplessness, improving the length and quality of sleep.

 


 

BERGAMOT AND GERANIUM MASSAGE BALM

The following is a recipe for a blend that can be used in an uplifting massage:

INGREDIENTS MEASURE
Cocoa Butter 15 g
Apricot Kernel Oil 85 ml
Bergamot Essential Oil 30 drops
Geranium Essential Oil 18 drops
Clary Sage Essential Oil 12 drops

INSTRUCTIONS:

  1. Melt the butter with the apricot kernel oil.
  2. Let it cool, then add the essential oils and mix thoroughly.
  3. Store in a clean container out of sunlight.

PRECAUTIONS:

  1. Do not use Bergamot before exposure to the sun.
  2. Avoid Geranium and Clary Sage oils during pregnancy.

 


 

    • Cocoa Butter: This moisturizer increases levels of endorphins and serotonin, providing a general emotional boost. The magnesium contained in the cacao is believed to prevent mood swings, and Phenylethylamine, which is a stimulant in the cacao, can lead to a keen sense of awareness, energy, and endurance.

 

    • Apricot Kernel Oil: This light, non-greasy, skin-softening oil is fast-absorbing and deeply penetrating. It soothes dry, irritated skin and locks in lasting moisture.

 

    • Bergamot Essential Oil: This energizing oil is known to boost blood circulation and to reduce nervous tension, stress, and anxiety, which in turn replaces negative mental states with feelings of joy, refreshment, and vigor. The relief of heavy emotional stressors such as sadness may lead to reduced blood pressure, relaxation, and better regulation of the sleep hormones serotonin and dopamine, which may lead to better sleep.

 

    • Geranium Essential Oil: The sweet, floral scent of this uplifting oil offers relaxation to body and mind. It is known to improve mental function and to boost the moods of those who suffer from anger, anxiety, and depression.

 

  • Clary Sage Essential Oil: This relaxing oil soothes nervous tension and reduces feelings of stress, boosting feelings of optimism. By relieving anxiety, it can help regulate sleep patterns and quality.

In Essence: Geranium Essential Oil

IN ESSENCE…

    • Pelargonium graveolens is the Geranium species that is most commonly cultivated for the extraction of the sweet-smelling essential oil.

 

    • Used in aromatherapy applications, Geranium Essential Oil reduces feelings of stress, anxiety, sadness, fatigue, and tension, enhances concentration, improves cognitive function, and balances the emotions as well as the hormones.

 

    • Used cosmetically or topically in general, Geranium Essential Oil is reputed to effectively eliminate dead cells, tighten the skin, promote the regeneration of new skin, and diminish signs of aging.

 

  • Used medicinally, Geranium Essential Oil works as an anti-inflammatory and antiseptic agent. It is reputed to enhance circulation, soothe symptoms of menstruation and menopause, reduce blood pressure and pain, and boost immunity.

HISTORY OF GERANIUM OIL

As early as the time of the ancient Egyptians, Geranium Oil has been used in a vast range of applications including the promotion of a clear, smooth, radiant complexion, the balancing of hormones, the alleviation of anxiety and fatigue, and the improvement of moods. When the Geranium botanical was introduced to Europe in the late 17th century, its fresh leaves were used in finger bowls. Traditionally, Geranium Essential Oil has been used as an insect repellent and it has also to flavor food, soft drinks, and alcoholic beverages.

Although this perennial shrub is indigenous to South Africa, the Geranium plant is now cultivated throughout the world, namely in Central America, Europe, the Congo, Egypt, Russia, and Japan. The Geranium species that is most commonly cultivated for the extraction of the sweet-smelling essential oil is Pelargonium graveolens. Depending on the country in which the specific varieties of Geraniums originate, Geranium Essential Oils may exhibit differing properties.

GERANIUM OIL BENEFITS

The main chemical constituents of Geranium Essential Oil are: Linalool, Geranyl formate, Citronellol, and Geraniol.

LINALOOL is believed to exhibit the following activity:

  • Sedative
  • Anti-depressant
  • Anti-inflammatory
  • Anti-anxiety
  • Anti-epileptic
  • Analgesic

GERANYL FORMATE is believed to exhibit the following activity:

  • Anti-fungal
  • Hepatoprotective
  • Aromatic (fresh, green, floral, fruity)

CITRONELLOL is believed to exhibit the following activity:

  • Anti-fungal
  • Sedative
  • Anti-viral
  • Anti-microbial
  • Anti-spasmodic
  • Anti-inflammatory
  • Anti-oxidant
  • Anti-convulsant

GERANIOL is believed to exhibit the following activity:

  • Anti-oxidant
  • Anti-bacterial
  • Anti-septic
  • Analgesic

Used in aromatherapy applications, Geranium Essential Oil is known to reduce feelings of stress, anxiety, sadness, fatigue, and tension, thereby enhancing the general sense of well-being and relaxation, while offering relief to those suffering from insomnia. Its sweet, uplifting floral scent makes it an ideal ingredient in the manufacturing of soaps and cosmetics, such as creams and perfumes. Furthermore, the scent of Geranium Oil is known to enhance concentration, improve cognitive function, and balance the emotions as well as the hormones. Its calming and tonic properties are known to regulate several body systems, including the respiratory and circulatory functions. This facilitates functions such as nutrient absorption and digestion, and as a result, it improves general health. When Geranium Oil is combined with any of the following essential oils, it is known to contribute to a blend that is aromatically appealing: Angelica, Basil, Bergamot, Carrot Seed, Cedarwood, Citronella, Grapefruit, Jasmine, Lavandin, Lavender, Lemon, Lime, Neroli, Orange, and Rosemary.

Used cosmetically or topically in general, Geranium Essential Oil is reputed to contribute to the health of the skin cells and ultimately the health of the complexion. It is known to effectively eliminate dead cells and to promote the regeneration of newer, healthier skin, thus benefitting the acne-prone skin. Its astringent property helps tighten the skin and to diminish the appearance of the symptoms of aging, such as sagging and wrinkling skin. For decades, Geranium Oil has also been used to promote hair growth by nourishing the scalp and balancing the production of sebum and natural oils.

Its anti-bacterial properties make Geranium Oil an ideal ingredient in cosmetic deodorants, as it eliminates body odor and leaves the body through perspiration.

When applied in a massage, Geranium Essential Oil is known to encourage muscles to contract, which firms the appearance of muscles and results in the body looking toned over time. By increasing collagen production, Geranium Oil is known to enhance elasticity and to maintain the skin’s softness and smoothness, which is especially beneficial on skin that has been exposed to chemicals, UV radiation, or rough physical activity. When used regularly, diluted Geranium Oil is also advantageous for strengthening loose, aging, or acne-prone skin. On scars, unwanted spots, blemishes, stretch marks, and cuts, Geranium Oil’s cicatrizant property is known to accelerate healing and fading. While boosting skin’s regenerative ability, it also evens out skin tone and the appearance of cellulite.

Used medicinally, Geranium Essential Oil works as an anti-inflammatory and anti-septic agent making it a beneficial ingredient for use in moisturizers that are meant to treat skin ailments such as excessive oil, acne, eczema, dermatitis, and psoriasis. It is reputed to enhance circulation, soothe symptoms of menstruation and menopause, and reduce blood pressure as well as pain. When applied to wounds, Geranium Oil is known to protect them against toxins and infections, which then allows the body to boost its immunity from within rather than directing its efforts to an external challenge. By creating blood clots, Geranium Oil stems the flow of blood, which accelerates the healing of wounds. It is reputed to address the discomforts of eczema, Athlete’s Foot and other fungal infections, burns, frostbite, and even sore throats.

 Geranium Oil is reputed to have many therapeutic properties. The following highlights its many benefits and the kinds of activity it is believed to show:

    • COSMETIC: Anti-Inflammatory, Relaxing, Balancing, Astringent, Deodorant, Tonic
    • ODOROUS: Anti-Inflammatory, Relaxing, Balancing, Decongestant, Deodorant, Anti-Depressant, Uplifting
  • MEDICINAL: Anti-Inflammatory, Relaxing, Astringent, Tonic, Anti-Viral, Anti-Bacterial, Decongestant, Anti-septic

GERANIUM OIL USES

Used in aromatherapy applications, the sweet scent of Geranium Oil is uplifting, energizing, and inspiring, offering a sense of positivity and good health, both physically and mentally. To diminish feelings of sadness and stress and to enhance cognitive function, diffuse 2-3 drops of Geranium Essential Oil in an essential oil diffuser. This has the added benefit of soothing a sore throat and addressing sinus infections.

For a cosmetic fragrance that balances the mood and that can be applied to the wrist, the inside of the elbows, and the neck in the same way as a regular perfume, first select a Carrier Oil of a personal preference. In a dry glass container, pour in 2 Tbsp. of the chosen Carrier Oil, then add 3 drops Geranium Essential Oil, 3 drops Bergamot Essential Oil, and 2 drops Lavender Essential Oil. Cover the container and shake it well to thoroughly blend all the oils together. To use this natural, homemade perfume, simply dab a few drops onto the aforementioned pulse points. Alternatively, a cosmetic fragrance can be made in the form of a natural deodorant by combining 5 drops of Geranium Essential Oil and 5 Tbsp. of water in a spray bottle. This refreshing and anti-bacterial body spray can be used daily to eliminate body odors.

Used in topical applications, Geranium Oil’s astringency makes it beneficial for tightening skin that is affected by symptoms of aging, such as wrinkles. To firm the appearance of sagging skin, simply add 2 drops of Geranium Essential Oil to a face cream and apply it twice daily until there are visible results. To tighten larger areas of skin, create a massage oil by diluting 5 drops of Geranium Essential Oil in 1 Tbsp. of Jojoba Carrier Oil before massaging it into the affected areas, concentrating especially on muscles that are likely to sag. Geranium Oil is reputed to not only tone the abdomen and support the growth of new skin but to also facilitate the efficacy of the metabolism.

geranium_captionimage

For a facial serum that that slows the look of aging, pour 2 Tbsp. of a Carrier Oil of personal preference into a dark 1 oz. glass dropper bottle. Recommended oils include Argan, Coconut, Sesame, Sweet Almond, Jojoba, Grapeseed, and Macadamia. Next, pour in 2 drops Geranium Essential Oil, 2 drops Lavender Essential Oil, 2 drops Sandalwood Essential Oil, 2 drops Rose Absolute, 2 drops Helichrysum Essential Oil, and 2 drops Frankincense Essential Oil. As each essential oil is added, gently shake the bottle to thoroughly incorporate it. Cleanse and tone the face before massaging 2 drops of the resultant serum into the face, focusing more on areas with fine lines, wrinkles, and age spots. When the product has absorbed into the skin, moisturize with a regular cream. When the product is not in use, store it in a cool and dark area.

For a gentle oil blend that enhances skin’s health and appearance, especially on skin afflicted by ailments such as acne and dermatitis, simply dilute 5 drops of Geranium Essential Oil in 1 tsp. of Coconut Carrier Oil. Next, gently massage this blend onto the affected area twice daily. It can be used every day until results are visible. Alternatively, 2 drops of Geranium Essential Oil can be added to a regular facial cleanser or body wash.

For a hair conditioner that gently hydrates and restores the natural pH of the scalp for strands that appear and feel softer and healthier, first combine 1 cup water, 2 Tbsp. Apple Cider Vinegar, and 10 drops of Geranium Essential Oil in a 240 ml (8 oz.) glass spray bottle or in a BPA-free plastic spray bottle. Shake the bottle vigorously to thoroughly blend all the ingredients together. To use this conditioner, spray it onto the hair, allow it to soak in for 5 minutes, then rinse it out. This recipe should yield 20-30 uses.

Used in medicinal applications, Geranium Oil is reputed to be ideal for addressing fungal and viral ailments, such as shingles, herpes, and Athlete’s Foot, as well as problems related to inflammation and dryness, such as eczema. For an oil blend that is moisturizing, soothing, and regenerative for feet affected by Athlete’s Foot, combine 1 Tbsp. Soya Bean Carrier Oil, 3 drops Wheatgerm Carrier Oil, and 10 drops Geranium Essential Oil in a dark bottle. To use, first soak the feet in a warm foot bath consisting of Sea Salt and 5 drops of Geranium Essential Oil. Next, apply the oil blend to the foot and massage it thoroughly into the skin. This can be done twice daily, once in the morning and again in the evening.

For an anti-bacterial bath that facilitates the elimination of bodily toxins and inhibits the onset of external contamination, first combine 10 drops Geranium Essential Oil, 10 drops Lavender Essential Oil, and 10 drops Cedarwood Essential Oil with 2 cups of Sea Salt. Pour this salt blend into a bathtub under hot running water. Before entering the tub, ensure that the salt has dissolved completely. Soak in this aromatic, relaxing, and protective bath for 15-30 minutes to stimulate better circulation and to promote the faster healing of blemishes, wounds, and irritations.

A Geranium Oil massage blend is known to ease puffiness, remove excess fluid in the skin and tissues, and firm sagginess. For a blend that tightens the skin and improves muscle tone, dilute 5-6 drops of Geranium Essential Oil in 1 Tbsp. Olive Carrier Oil or Jojoba Carrier Oil and gently massage it over the entire body before taking a bath or shower. For a calming massage blend that is reputed to address muscle tension and nerve pain, dilute 3 drops of Geranium Essential Oil in 1 Tbsp. of Coconut Carrier Oil. This blend is also beneficial for issues with inflammation, such as arthritis.

For an anti-microbial remedy that not only soothes and disinfects scrapes, cuts, and wounds, but that also quickly stops the bleeding, dilute 2 drops of Geranium Essential Oil in water and wash the affected area with this mixture. Alternatively, Geranium Essential Oil can be diluted in 1 Tbsp. of Olive Carrier Oil and spread in a thin layer on the affected area. This application can be continued daily until the wound or irritation heals or clears up.

Alternatively, a remedial salve can be made with the addition of several other healing essential oils: First, place a double boiler on low heat and pour 30 ml (1 oz.) Beeswax into the upper half of the double boiler until the wax melts. Next, add ¼ cup Almond Carrier Oil, ½ cup Jojoba Carrier Oil, ¾ cup Tamanu Carrier Oil, and 2 Tbsp. Neem Carrier Oil and stir the mixture. Remove the double boiler from the heat for a few minutes and allow the blend to cool down without allowing the Beeswax to harden. Next, add the following essential oils, making sure to whisk in each one thoroughly before adding the next: 6 drops Geranium Essential Oil, 5 drops Lavender Essential Oil, 5 drops Cedarwood Essential Oil, and 5 drops Tea Tree Essential Oil. When all the oils have been added, mix the combination once more to ensure complete blending, then pour the final product into a tin car or a glass jar. Continue stirring the blend occasionally and allow it to cool. This can be applied in a small amount to cuts, wounds, scars, and bug bites. When the product is not in use, it can be stored in a cool and dry area.

Geranium Oil is known to provide relief for feminine issues such as the discomforts associated with menstruation. For a relieving massage blend that soothes the uneasy symptoms, such as pain, soreness, and tightness, first, pour ½ cup of a Carrier Oil of personal preference into a clean and dry bottle. Recommended Carrier Oils include Sweet Almond, Grapeseed, and Sunflower. Next, add 15 drops Geranium Essential Oil, 12 drops Cedarwood Essential Oil, 5 drops Lavender Essential Oil, and 4 drops Mandarin Essential Oil. Cap the bottle, gently shake it to thoroughly combine all the ingredients, and allow it to sit overnight in a cool and dry area. To use this blend, gently massage a small amount of it onto the skin of the belly and the lower back in a clockwise direction. This can be used daily for a week leading up to the beginning of the menstrual cycle.

A GUIDE TO GERANIUM OIL VARIETIES & THEIR BENEFITS

GERANIUM ESSENTIAL OIL (BOURBON)

Botanical Name: Pelargonium graveolens L’Her.

Method of Extraction and Plant Part: Steam distilled from leaves & flowers

Country of Origin: China

Believed to:

  • Have the same therapeutic properties as other varieties of Geranium Oil, but to be the preferred variety among aromatherapists, due to its more preferable fragrance
  • Be both mentally and physically balancing, soothing, and regulating
  • Stabilize hormones and negative moods
  • Regulate sebum production in both dry and oily skin
  • Promote cell regeneration
  • Encourage blood clotting to promote the faster healing of wounds
  • Enhance immunity and boost resistance to stress
  • Have uplifting properties that enhance the mood to reduce feelings of anxiety, nervousness, irritability, and sadness
  • Exhibit deodorizing and disinfecting properties
  • Reduce the appearance of cellulite

GERANIUM ESSENTIAL OIL (EGYPTIAN) / GERANIUM ORGANIC ESSENTIAL OIL

Botanical Name: Pelargonium graveolens Pelargonium x asperum

Method of Extraction and Plant Part: Steam distilled from leaves & flowers

Country of Origin: Egypt

Believed to:

  • Balance and enhance the complexion
  • Be ideal for use in addressing feminine ailments related to reproductive health
  • Have uplifting properties that enhance the mood to reduce feelings of anxiety, nervousness, irritability, and sadness
  • Exhibit astringent properties that cause the skin, tissues, and muscles to contract in order to leave the face and body looked clear, toned, and tightened
  • Stimulate and enhance circulation
  • Have anti-oxidant, anti-fungal, and anti-bacterial properties that may prevent viral infections
  • Facilitate the body’s elimination of toxins
  • Enhance digestion and reduce the chances of developing flatulence

ROSE GERANIUM ORGANIC ESSENTIAL OIL

Botanical Name: Pelargonium roseum x asperum

Method of Extraction and Plant Part: Steam distilled from leaves

Country of Origin: South Africa

Believed to:

  • Have the same therapeutic properties as other varieties of Geranium Oil
  • Usually be used in combination with other floral essential oils, often with Lavender, or to soften more herbaceous scents
  • Often be used to extend the more expensive Rose Oils or the endangered Rosewood Oil, when it is available.
  • Be a staple ingredient for formulators who rely on essential oils for their high-end fragrance profiles

ROSE GERANIUM SOUTH AFRICAN ESSENTIAL OIL

Botanical Name: Pelargonium roseum X asperum

Method of Extraction and Plant Part: Steam distilled from petals

Country of Origin: South Africa

Believed to:

  • Have the same therapeutic properties as other varieties of Geranium Oil
  • Be one of the most fragrant species of Rose Geranium
  • Be used in perfumery and in the cosmetics industry, as it can be made to imitate many other fragrances
  • Be often used to ‘stretch’ the scent of much more expensive Rose Oils

CONTRAINDICATIONS FOR GERANIUM OIL

Geranium Oil should never be ingested due to its toxicity. It is imperative to consult a medical practitioner before using this oil for therapeutic purposes. Pregnant and nursing women are especially advised not to use Geranium Essential Oil without the medical advice of a physician, as it may have an effect on certain hormone secretions and it is unclear whether these effects are transferable to babies at these stages of development. The oil should always be stored in an area that is inaccessible to children, especially those under the age of 7.

Due to Geranium Oil’s styptic property, those with the following health conditions are recommended to be advised: diabetes, cancer, high blood pressure and other heart-related ailments, peptic ulcers, liver damage, bleeding disorders, skin disorders, or hormone-related ailments. Individuals that are taking prescription drugs, undergoing major surgery, or who are at a greater risk of experiencing strokes, heart attacks, or atherosclerosis are also advised to seek medical consultation prior to use.

Prior to using Geranium Oil, a skin test is recommended. This can be done by diluting 1 drop of the Essential Oil in 4 drops of a Carrier Oil and applying a dime-size amount of this blend to a small area of skin that is not sensitive. Geranium Oil must never be used near the eyes, inner nose, and ears, or on any other particularly sensitive areas of skin. Potential side effects of Geranium Oil include sensitization, rashes, and a burning sensation.

Those seeking medical care to manage moods, behaviors, or disorders should treat this essential oil as a complementary remedy rather than a replacement for any medicinal treatments or prescriptions. In the event of an allergic reaction, discontinue use of the product and see a doctor, pharmacist, or allergist immediately for a health assessment and appropriate remedial action. To prevent side effects, consult with a medical professional prior to use.

 

Anticancer Properties of Essential Oils and Other Natural Products

Received 27 October 2017; Accepted 13 February 2018; Published 25 March 2018
Review Article
Volume 2018 (2018), Article ID 3149362, 12 pages
https://doi.org/10.1155/2018/3149362

Essential oils are secondary metabolites with a key role in plants protection, consisting primarily of terpenes with a volatile nature and a diverse array of chemical structures. Essential oils exhibit a wide range of bioactivities, especially antimicrobial activity, and have long been utilized for treating various human ailments and diseases. Cancer cell prevention and cytotoxicity are exhibited through a wide range of mechanisms of action, with more recent research focusing on synergistic and antagonistic activity between specific essential oils major and minor components. Essential oils have been shown to possess cancer cell targeting activity and are able to increase the efficacy of commonly used chemotherapy drugs including paclitaxel and docetaxel, having also shown pro-immune functions when administered to the cancer patient. The present review represents a state-of-the-art review of the research behind the application of EOs as anticancer agents both in vitro and in vivo. Cancer cell target specificity and the use of EOs in combination with conventional chemotherapeutic strategies are also explored.

1. Introduction

Whilst some synthetic compounds unequivocally have an important role in disease prevention and therapy, there is also an extensive collection of naturally existing compounds that have been exploited for their unique medicinal purposes [1]. The use and demand of natural compounds have been increasing worldwide, showing their importance, which can be attributed to relevant medicinal properties [2]. Essential Oils (EOs) and other phytoproducts are examples of natural products that have gained interest, mainly due to their suitable chemical characteristics and biological activities [3].

As stationary organisms, plants have evolved a diverse range of protective mechanisms to lessen their vulnerability against external threats. These mechanisms can be classified as physical and chemical defenses. Physical deterrents include protective structural characteristics, which include waxy barriers, spikes, and “hair-like” trichomes, which release chemical compounds [4]. Chemical defense mechanisms include, for example, the production of a range of defensive metabolites bioactive compounds with the capability to repulse herbivores or even to target their endocrine and nervous system [56]. These include EOs, enzymes, tannins, and flavonoids, amongst others. Importantly, these compounds are also of pharmacological interest.

EOs are complex and multifunctional substances with plant origin, which have been used for thousands of years for their role in the prevention and treatment of various ailments [378]. Chemically, EOs are aromatic plants secondary metabolites with several roles: defense against herbivores, insects, and microorganisms; communication with plants of the same species; and signaling within the plant in response to environmental stimuli [5]. As each plant species or subspecies has evolved to protect itself from a particular predator or group of predators, each plant produces its own specific “signature” mixture of EO chemical constituents [57]. This can contain from 20 to 60 constituents at varying concentrations, with two or three primary constituents (20–70%) [910].

1.1. Chemical Composition of EOs

There are approximately 3000 EOs, with over 2000 different plants, with around 300 EOs possessing known biomedical features [21011]. Together with the plant species, the developmental stage (flowering, fruiting) and aromatic compound extraction methods have a direct influence on the composition of EOs, which explains the variability of components in the reported EOs [12].

Based on their chemical compositions, EOs are broadly categorized into oxygenated compounds and hydrocarbons [9]. Oxygenated compounds include esters, aldehydes, ketones, alcohols, phenols, and oxides. Other active groups include aromatics and sulfur-containing components [91224]. Hydrocarbon compounds are composed of one specific chemical group called terpenes (Figure 1) [9]. These are composed of varying numbers of isoprene units (C5). Monoterpenes (C10) and sesquiterpenes (C15) are the main terpenes, although the isoprene chains may also include diterpenes (C20). Monoterpenes contribute to 90% of EO overall constituents [9]. Both monoterpenes and sesquiterpenes offer a large variety of structures through adjoining with other biologically active functional groups (monoterpenoids), and chemical rearrangement and addition of oxygenated groups (sesquiterpenoids) [9]. Terpenes may also be acyclic, monocyclic, or bicyclic and may contain an aromatic group [9]. The longer the isoprene chain, the more the chemical variations possible [924]. The structures of several medicinally important terpenes are illustrated in Figure 1.

Figure 1: Chemical structures of essential oil constituents.

Due to the large range and complex blend of EOs constituents, as well as their many functional groups, it is thought that EOs do not possess a specific single cellular target, with each complex mixture initiating different cellular effects through their major constituents [910]. However, it is important to consider the minor constituents of an EO, and the different cellular effects exhibited when the constituents are combined in the EO blend versus the isolated constituents. A study performed by Santana-Rios and coworkers (2001) isolated the main constituents of both white and green tea and created an artificial “mixed” tea with a total of 9 main constituents [25]. The artificial tea exhibited a lesser antimutagenic effect than the whole tea extracts in the Salmonella assay in the presence of -hydroxy-IQ, a potent mutagen. Furthermore, it has been shown that EOs extracted from the tea tree, eucalyptus, and thyme plants reduced Herpes simplex virus- (HSV-) 1 viral infectivity by more than 96% in an in vitro study through inactivation of virus-free particles, with the combined EO constituents more effective than the isolated counterparts [26]. Recent studies also have been pointing out the therapeutic potential of the individual constituents of EOs, such as the work of Dias and colleagues (2017), which showed a possible association between the oxygenated monoterpenes of EOs extracted from Lavandula luisieri and Cymbopogon citratus and the antifungal activity against dermatophytes [27]. This was because an inhibitory effect was observed on the conidial germination, demonstrating the strong antifungal activity of these EOs components [27]. The mentioned studies indicate that minor constituents possess both synergistic and antagonistic activities on the major constituents, playing an important role in the overall properties of EOs on a variety of cell types.

1.2. EOs as Therapeutic Agents

Only 5 to 15% higher order plants have been addressed for their bioactive compounds [28]. As EOs are a coevolutionary product of plants, functioning to protect them from herbivore attack, they often elicit undesirable and potentially harmful effects on animal cells and bodily functions [5]. However, these undesirable effects of EOs can be exploited and used to treat diseases and symptoms. Examples include emetics and laxatives, muscle relaxants, cardiac stimulants, and cardiac depressants resulting in hypotension and induction of bradycardia [8].

Atherosclerosis is the arterial build-up of fats and other compounds and is a large contributor to thrombosis and arterial occlusion [29]. The main driver of this disease is the oxidation of low-density lipoproteins (LDLs), and it was shown that phenolic-rich EOs such as thymol and eugenol exhibit the highest LDL antioxidative effect, with their capabilities increased through also reducing LDLs’ affinity for the LDL receptor [7]. Other benefits for treating cardiovascular disease, thus reducing the risk of atherosclerosis, include the reduction of cholesterol and triglyceride levels in plasma, in which black cumin oil achieved this reduction in rats over a period of 12 weeks, with low toxicity and no adverse effects in kidneys or liver [7]. Additionally, recent studies have demonstrated the capability of EOs to act on inflammatory and other cellular processes associated with cardiovascular diseases, by preventing the secretion of proinflammatory factors through the reduction of lipopolysaccharide (LPS) [3031]. EOs may be used in both analgesics and anti-inflammatories, such as black cumin and eucalyptus oils [3233]. It is clear, with respect to recent research, that Eos’ ability to bind various cellular receptors has therapeutic value and potential for both treatment of infectious diseases, and for inborn and intrinsic diseases. Importantly, these mechanisms of action of EOs leading to cellular and metabolic responses make them attract new sources of anticancer therapeutic strategies.

The aim of this review is to evaluate the research behind the application of EOs as anticancer agents, both in vitro and in vivo. Cancer cell target specificity without noncancerous tissue toxicity will be explored, as well as the use of EOs in combination in conventional chemotherapeutic strategies.

2. Anticancer Proprieties of EOs

According to the International Agency for Research on Cancer (IARC), in 2012 there were 14.1 million new cancer cases worldwide and 8.2 million cancer deaths [34]. Cancer is now the leading cause of death and is expected to increase by 70% in the next two decades, with lung, liver, stomach, colorectal, breast, prostate, and oesophageal cancer accounting for most of the deaths [3435]. These statistics support the need for new and novel chemotherapeutic drugs in the coming years.

Cancer is broadly divided into three stages: (1) initiation, in which cellular DNA damage and mutation occur on carcinogen exposure and due to failure of DNA repair mechanisms; (2) promotion, in which hyperproliferation, tissue remodelling, and inflammation occur due to expansion of initiated cell/s; and (3) progression, in which preneoplastic cells form tumors through clonal expansion, further facilitated by an increase in genomic instability and altered gene expression [36]. The different stages of carcinogenesis require different chemotherapeutic approaches, due to the evolutionary nature of cancer, which lead to alterations in sensitivity to therapy. Specifically, tumour progression is associated with genomic instability, through accumulation of mutations for factors involved in cell proliferation, apoptosis, and DNA repair, amongst others [3637]. Chemotherapy drugs act on the promotion stage, in ways including cellular proliferation inhibition, increased rate of cell death, and induction of tumor cell differentiation [38].

Although research on the application of EOs as anticancer therapeutic agents is relatively new, approximately half of conventional chemotherapy agents have plant origin, with roughly 25% directly derived from plants, and 25% being chemically modified versions of phytoproducts [28]. One such molecule is paclitaxel. Paclitaxel (of which the most common brand name is Taxol) was originally derived from the bark of the tree Taxus brevifolia[39]. Its mechanism of action is based on the induction of a mitotic arrest via the targeting of the cytoskeleton component tubulin, resulting in mitotic checkpoint activation, and subsequent apoptosis [39]. It is used as a therapeutic agent either as a single agent or in combination therapy strategies for various cancer types, including ovarian, breast, and pancreatic cancer [39]. Laboratory synthesis of this drug was needed due to depletion of the natural source, primarily through a synthesis route involving EO constituent patchoulol (Figure 1) to produce patchoulol oxide [40]. More recently, Altshuler and collaborators found that the enantiomer (+)-citronellal, a major component of Corymbia citriodora and Cymbopogon nardus EOs, is also an effective microtubule-disrupting compound, similarly to better-known microtubule-disrupting agents colchicine and vinblastine [41].

EOs have been shown to possess anticancer properties through various mechanisms, including cancer preventative mechanisms, as well as acting on the established tumor cell itself and interaction with the microenvironment (Figure 2) [742].

Figure 2: Essential oils cancer preventative and anticancer mechanisms of action. EOs possess antimutagenic, antiproliferative, antioxidant, and detoxifying capabilities acting on various pathways in the cancer cell as well as cancer preventative capabilities. EOs may directly inhibit mutagen entry into the cell. EOs can decrease phase I enzymes such as CytC, preventing mutagen formation, and increase phase II enzymes such as GST, UGT, QR, and EH for enhanced detoxification. EOs bind ROS forming reactive phenoxy radicals which bind further ROS and increase antioxidative enzymes CAT, SOD, GPx, and GSH thus preventing oxidative damage as a cancer preventative mechanism. EOs disrupt mitochondrial membrane potential causing an increase in ROS and decrease in GSH, the release of CytC, resulting in a cascade of disruption in Bcl/Bax ratio, increase in caspase 3 and caspase 9 activity, and PARP cleavage, resulting in apoptosis. EOs suppress mTOR and pPDK1 causing PKB dephosphorylation, which dually acts to initiate caspase activity and deactivate mdm2, causing an increase in p21 to further initiate caspase activity resulting in apoptosis. Increased p21 also induces G1/S phase cell cycle arrest. EOs cause a decrease in CDK7, blocking CDK1/cyclin complex causing G2/M phase cell cycle arrest. Bax: B-cell lymphoma 2-associated X protein; Bcl-2: B-cell lymphoma 2; CAT: catalase; CDK: cyclin-dependant kinase; CytC: cytochrome C; CytP450: cytochrome P450; EH: epoxide hydrolase; EO: essential oil; ER: endoplasmic reticulum; ETC: electron transport chain; GPx: glutathione peroxidase; GSH: glutathione; GST: glutathione S-transferase; mdm2: murine double minute 2; mTOR: mechanistic target of rapamycin; MITO: mitochondria; NFκB: nuclear factor-κB; PARP: poly ADP ribose polymerase; pPDK1: protein pyruvate dehydrogenase kinase 1; PKB: protein kinase B; QT: quinone reductase; ROS: reactive oxygen species; SOD: superoxide dismutase; UGT: uridine 5′-diphospho-glucuronosyltransferase.
2.1. Antimutagenic Proprieties and Detoxification Enhancement

EO cancer preventative mechanisms include direct inhibition of the mutagen entering the cell, although underlying mechanisms remain unexplained [743]. Other cancer preventives and antimutagenic properties include a decrease of enzymes involved in drug metabolism. These include phase I enzymes such as cytochrome P450 [4445]. Phase II enzymes are responsible for detoxification and are mainly comprised of transferases [46]. Glutathione -transferase (GST), uridine 5′-diphospho-glucuronosyltransferase (UGT), quinone reductase (QR), and epoxide hydrolase (EH) were observed to be increased on sulfur-containing EO activity such as that from garlic and onions [4752]. The EO component citral, a monoterpene obtained from plants such as lemongrass, has been shown to induce phase II enzymes in a dose-dependent manner [53]. The mechanism of action of citral is due to its geranial isoform component [53]. Recent studies have shown citral to inhibit cell proliferation and tumor growth by increasing the intracellular levels of oxygen radicals and, consequently, inducing oxidative stress, leading to the reduction of cancer cell proliferation and ultimately resulting in cell death [5455].

2.2. Antiproliferative Mechanisms of Action of EOs

Key hallmarks of cancer include resisting cell death, sustained proliferative signaling, and evading growth suppressors [28]. Therefore, therapeutic strategies focused on inducing apoptosis and cellular arrest are of clear significance. EOs have been shown to induce both the intrinsic (or mitochondria-dependent) and extrinsic (or death receptor-dependent) apoptosis pathways.

Girola and coworkers (2015) tested the antitumor properties of a camphene isolated from the EO of Piper cernuum in melanoma cells. The study demonstrated that this compound was able to induce apoptosis through the caspase-3 pathway activation, as well as activating the endoplasmic reticulum (ER) stress signaling [56]. Another study focused on the evaluation of the mechanism of action of carvacrol, a phenolic monoterpenoid abundant in the EOs of oregano and thyme [57]. In the metastatic breast cancer cell line MDA-MB-231, carvacrol induced apoptosis via mitochondrial membrane permeabilization, resulting in cytochrome C release, induction of caspases indicated through poly ADP ribose polymerase (PARP) cleavage, and DNA fragmentation [57]. Frankincense extracts obtained from Boswellia sacra induced PARP cleavage with apoptosis in MDA-MB-231 cells, with higher cancer cell specificity [14]. Citral was also shown to induce caspase activation and subsequent apoptosis induction in several cancer cell types, including colorectal cancer and glioblastoma [5860]. Other studies have shown that citral treatment can lead to the reduction of expression of prostemness and prosurvival factors such as aldehyde dehydrogenase 1A3 (ALDH1A3) and microtubule affinity regulating kinase 4 (MARK4) in cancer, respectively [6162].

PKB (Protein kinase B) is a key molecule with roles regarding cellular metabolism, transcription, cell cycle progression, and survival [63]. The vapor of Litsea cubeba seed oil induced cell cycle arrest and apoptosis of nonsmall cell lung carcinoma cells, a cancer type with a high mortality rate [64]. In this study, apoptosis occurred due to a significant decline in the expression of mTOR (mechanistic target of rapamycin) protein, and a decline in the phosphorylating ability of PPDK1 (protein pyruvate dehydrogenase kinase 1), leading to dephosphorylation of PKB and initiating the caspase-dependent apoptosis pathway [64]. Furthermore, PKB dephosphorylation inactivated mdm2 (murine double minute 2), leading to an increase in p21 expression, and subsequent caspase initiation after G1/S phase arrest [64]. This dual mechanism offers antiproliferative as well as antioxidant proprieties, and the vapor can be inhaled directly to the site of cancer in the lung, offering a clear advantage in administration [64].

Wu and colleagues showed that administering organosulphur components of garlic significantly decreased cell viability () compared with control in a dose and time-dependent manner, with diallyl trisulphur being the most effective [65]. This was observed in J5 liver tumor cell line through a G2/M cycle arrest, leading to cell death via a decrease in expression of cyclin-dependent kinase (CDK) 7 and subsequent CDK1/cyclin complex inhibition [65].

Expression of NFκB (nuclear factor-κB) is abnormally increased in cancer cells and is particularly associated with cancer initiation and progression [6668]. α-terpineol, a monoterpenoid alcohol, was able to downregulate the transcription of NFκB in a range of tumor cells, with the strongest inhibitory effect on small cell lung carcinoma cell line NCI-H69 [69]. Finally, α-terpineol was further shown to have synergistic properties with another monoterpene, linalyl acetate, in colon cancer cells, inhibiting NFκB expression and resulting in apoptosis [70].

2.3. Antioxidant Proprieties of EOs

Mitochondrial DNA damage can result from oxidative stress, and defects on the electron transport chain (ETC) result in the further release of reactive oxygen species (ROS) and further DNA, lipid, and protein damage [71]. Antioxidant properties of EOs can, therefore, contribute to cancer preventative mechanisms [3672]. Specific EO components such as eugenol, the main constituent extracted from clove oil, can react with ROS to form reactive phenoxy radicals, which can then combine with further ROS and prevent further damage [73]. Other cancer protective mechanisms induced by EOs include the induction of the expression of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and glutathione, as shown by Manjamalai and Berlin Grace [74]. Treatment with EO extracts of Wedelia chinensis (96% of the components being carvacrol and trans-caryophyllene) lead to an increase in intracellular antioxidant activity, subsequently leading to a significant reduction in tumor mass volume as well and regeneration of surrounding healthy tissue [74].

However, research by Le Gal and colleagues (2015) showed that increased intracellular antioxidant activities can actually increase tumor cell survival, both using in vitro and in vivo models [75]. Specifically, oxidized glutathione, an indicator of oxidative stress levels, was increased on antioxidant administration, thus offering protection for the melanoma metastasis cancer cells [75]. This is a similar mechanism as the one observed with conventional chemotherapy drug methotrexate, which is a prooxidant and increases cellular glutathione levels [76]. Therefore, EO extracts with these types of antioxidant properties are likely to be more beneficial as chemopreventive agents for nontumor tissue.

Finally, Legault and colleagues (2000) showed that balsam fir oil extracts led to decreased glutathione levels, mediated by the EO component gamma-caryophyllene, which promotes ROS increase and glutathione decrease due to α-humulene in a dose-dependent manner [77].

3. Cancer Cell Specificity of Essential Oils

Conventional chemotherapy drugs are more cytotoxic to cancer cells due to their higher rate of cell division; however, due to this mechanism of action, there are issues with tumor cell specificity and associated cytotoxicity to healthy cells [78]. The subsequent side effects in the patient can hinder recovery and even prove to be life-threatening. Currently, combined therapeutic approaches of surgery followed by chemotherapy, radiotherapy, and immunotherapy offer increased chances of treating cancer and remission [78]. However, this does not address the need for cancer cell-specific therapy, or an increased therapeutic window between normal and cancer cells. Novel targeted strategies are a significant improvement but still have issues with cell specificity, and more importantly, a very high attrition when moving these agents from preclinical studies to clinical applications [78]. The use of monoclonal antibodies is highly selective, though it has limited cytotoxic activity [79]. Combined administration of monoclonal antibodies and conventional chemotherapy drugs is one potential route for solving this problem, delivering the highly cytotoxic agent specifically to cancer cells [79].

The use of EOs extracts as single agents has been shown in various in vitro studies to specifically target cancer cells, with absent or markedly less cytotoxicity exhibited towards healthy cells with a range of mechanisms of action (Table 1).

Table 1: Essential oils bearing plants and main constituents with targeted cancer cell cytotoxicity in in vitro studies.

Boswellia sacra extracts have shown very promising results in vitro and in vivo. Boswellia sacra extracts were shown to be cytotoxic to three breast cancer cell lines (T47D, MCF7, and MDA-MB-231) at varying concentrations, which were noncytotoxic to immortalized normal human breast cells MCF10-2A [14]. This study also showed that Boswellia sacra extracts that were hydrodistilled for 12 hours at 100°C were more potent than the essential oil extracts prepared at 78°C, with a higher amount of boswellic acid present. Apoptosis markers activated caspase 3 activity, PARP cleavage, and DNA fragmentation rapidly in MDA-MB-231 but not MCF10-2A cells [14]. Importantly, treatment with the extracts blocked the growth of multicellular tumor spheroids from T47D, indicating the potential for efficacy in in vivo models [14]. Similarly, Boswellia sacrashowed cell-specific cytotoxicity in a dose-dependent manner to bladder transitional cell carcinoma cell line J82, in contrast to no cytotoxicity observed in normal bladder cell line UROtsa [17]. Treatment of J82 cells rapidly led to cell shrinkage and detachment from the plate, whereas no changes were observed for UROtsa cells. This effect was associated with decreased expression of 47 genes after treatment with the EO extracts, whose functions include transcription factors, cell cycle regulation, and cell proliferation [17]. Finally, Boswellia sacra also showed cytotoxicity towards human pancreatic cells, both cultured and in a xenograft mouse model, exhibiting repression of cell cycle regulators and activation of the caspase pathway in in vitro cultures, and causing decreased tumor cell growth and tumor cell death in vivo [80]. Similarly, to the work by Suhail et al. (2011) [14], EO extract potency was increased with the increase of hydrodistillation temperature, associated with the extraction of higher levels of boswellic acids and sesquiterpenes, which is indicated to be positively correlated with cytotoxicity [80].

EO extracts from Amomum tsaoko exhibited cytotoxicity towards various human cancer cell lines, including liver cancer (HepG2 and Bel-7402), cervical cancer (HeLa), gastric adenocarcinoma (SGC-7901), and prostate cancer (PC-3) [15]. Importantly, these extracts were less effective towards normal hepatocytes HL-7702 and umbilical vein endothelial (HUVEC) cell lines [15]. The individual components of this EO mixture, eucalyptol and geraniol, were also tested [15]. Eucalyptol was not cytotoxic to any cancer cell line, and geraniol exhibited a minimal cytotoxic effect towards all cancer cell lines but was markedly lower than the complete EO mixture [15]. Synergism of eucalyptol and geraniol with each other and/or other EO components, therefore, must contribute to the cytotoxic activity [15].

4. Synergism of EO Extracts with Conventional Chemotherapeutic Agents: Potential of Combination Therapy Using EOs

Specific EO constituents have been shown to enhance the cytotoxic activity of chemotherapy drugs in various cell lines (Table 2), thus increasing the therapeutic window, that is, lowering the required drug concentrations whilst providing the same effect [2223].

Table 2: In vitro studies of essential oils in combination with conventional chemotherapy agents.

Docetaxel is the first line therapy for hormone-refractory prostate cancer, which has a median survival of 20 months [22]. Docetaxel is associated with serious side effects and is currently used in combination with treatment exhibiting dose-dependent toxicity to the patient [22]. -limonene showed cytotoxic activity alone towards prostate cancer cell line DU-145, and when administered alongside docetaxel, sensitized the cells towards this drug in a dose-dependent manner allowing for a markedly lower dose of docetaxel to be used, achieving the IC50 in concentrations from 2.8 nM to 1.9 mM [22]. Limited toxicity was also shown towards normal prostate epithelial cells. Further analysis on the effects of combined treatment showed an increase in ROS production from both mitochondrial dependent and independent pathways, as well as increased cytochrome C release, p53 stabilisation, and caspase and PARP cleavage after 0-48 hours [22]. In addition to decreasing the amount of toxic docetaxel required, d-limonene showed low toxicity towards humans. It is possible that this combination may also be effective in docetaxel-resistant cell lines [22].

β-caryophyllene, which was not cytotoxic as a single agent, was shown to markedly increase the cytotoxic activity of paclitaxel in various cancer cell lines (Table 2). Specifically, the largest effect was observed on DLD-1 cells treated with paclitaxel combined with 10 μg/mL−1β-caryophyllene, increasing paclitaxel activity approximately 10 times [23]. It was shown that β-caryophyllene increased cell membrane permeability for paclitaxel uptake, likely due to β-caryophyllene accumulation in the lipid bilayer, and thus altering the permeability for substances such as paclitaxel [23].

Neutropenia is a common side effect of both cancer itself and therapies including chemotherapy and radiotherapy, the latter especially if targeted to active sites of bone marrow proliferation [81]. Cancer-related neutropenia has a high mortality rate due to susceptibility to infectious diseases, particularly from gram-negative bacterial infections, and combined with fever is considered an oncological emergency [81]. Currently, there are limited adjunctive treatments, one of which is the administration of granulocyte colony-stimulating factors (G-CSFs), in selected patients only, which promotes bone marrow production of granulocytes [81]. Alternatively, chemotherapy dose-modification may be deemed appropriate [81]. A study by Zhuang and coworkers (2009) which included 105 cancer patients with nonterminal breast, colorectal, nasopharyngeal, or lung cancer showed significant results in preventing the depletion of leukocytes (14.2%) and neutrophils (11%), versus control (29.1%) over a 6-week period [82]. Flow cytometry analysis showed a larger depletion of CD4 and natural killer cells in the placebo receiving group versus the Chinese medicinal herb complex (CCMH) receiving group [82]. The largest component of the CCMH was the EO component citronellol (273.6 mg per capsule), a known strong antioxidative compound, also exhibiting anticancer and anti-inflammatory properties, as well as promoting wound healing [82]. It is not clear from this study how exactly citronellol and each other component contributed to results. So, to date the mechanism of action remains to be elucidated.

Geraniol has been shown previously to sensitize cancer cells to the conventional chemotherapeutic agent 5-fluorouracil (5-FU), also causing an increased uptake of the drug [8384]. Geraniol has also been shown to be chemoprotective towards normal colon cells in rats when administered with the potent carcinogen dimethylhydrazine [85]. This effect occurs through mediating the reduction of DNA damage when compared with controls where no EO extract was used [85].

5. Conclusions and Future Directions

EO have been shown to possess a wide range of anticancer properties and mechanisms. Considering the myriad of components present and the mechanism and synergistic capabilities of EO extracts, it is of paramount importance to perform further studies regarding evaluation on how EO minor components contribute to the overall effect of the EO extract mixture. Further in vitro and in vivo research into achieving the most effective cytotoxic EO mixture composition would allow for more targeted therapy, and with increased specificity to cancer cells over non-cancer tissue. Furthermore, the currently used concentrations of conventional chemotherapy drugs could potentially be reduced combined with specific EO, which could also decrease chemotherapy-associated toxicity. Moreover, synthetic modification of these molecules may allow improving their overall efficacy further. However, there is still a significant lack of preclinical studies for EOs as anticancer agents; thus many EOs require further safety and toxicity studies before they can take part in clinical trials.

Cancer cell specificity is a sought-after propriety that is lacking in conventional chemotherapeutic strategies [7986]. As well as addressing cellular specificity, another strategy to increase cell specificity includes novel drug delivery strategies [86]. Specifically, a new field addressing this involves the use of microspheres made of proteins or synthetic polymers containing the anticancer agent or EO, for delivery to the specific organ or another site of cancer [86]. These can be administered intravenously or intra-arterially depending on the target site [86]. The use of microspheres has promising potential due to multiple types of drugs being successfully contained and delivered in a single vehicle, offering the potential for combination therapies, but also, the use of nanoemulsions is an improvement to transport and to deliver the EOs with anticancer properties, improving their therapeutic effect [87]. Cancer cell specificity can also be enhanced by the use of ligands added to the surface, targeting overexpressed cell surface proteins on the cancer cell [88]. Crucially, EOs can be degraded through physical, chemical, or enzymatic processes, so microsphere encapsulation may prevent this for optimised delivery [8889]. This way, EOs and other drugs may be released in a controlled manner, potentially reducing excess dosage and increasing the overall safety of these constituents, and offering a promising strategy for targeted drug and EO delivery to cancer cells [89].

In conclusion, although this is a relatively new and emerging area of cancer research, the ability of EOs and their components of having such diverse anticancer effect through acting on various pathways and cellular mechanisms is compelling. Thus, it is warranted that more studies be performed to expand the present knowledge of these mechanisms with the aim of promoting cell-specific and individualized cancer therapy.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

K. Blowman and M. Magalhães contributed equally to this work.

Acknowledgments

This work was supported through HEFCE funding provided by the University of Hull (I. M. Pires, K. Blowman), by a Fundação para a Ciência e Tecnologia Strategic Project UID/MAR/04292/2013 Grant to MARE, the European Union through EASME Blue Labs project AMALIA (EASME/EMFF/2016/1.2.1.4/03/SI2.750419), and by the Integrated Programme of SR&TD “SmartBioR” (reference Centro-01-0145-FEDER-000018), cofunded by Centro 2020 program, Portugal 2020, European Union, through the European Regional Development Fund.

References

  1. Y. Bhalla, V. K. Gupta, and V. Jaitak, “Anticancer activity of essential oils: a review,” Journal of the Science of Food and Agriculture, vol. 93, no. 15, pp. 3643–3653, 2013. View at Publisher · View at Google Scholar ·View at Scopus
  2. J. S. Raut and S. M. Karuppayil, “A status review on the medicinal properties of essential oils,” Industrial Crops and Products, vol. 62, pp. 250–264, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. A. E. Asbahani, K. Miladi, W. Badri et al., “Essential oils: From extraction to encapsulation,” International Journal of Pharmaceutics, vol. 483, no. 1-2, pp. 220–243, 2015. View at Publisher · View at Google Scholar· View at Scopus
  4. J. Fürstenberg-Hägg, M. Zagrobelny, and S. Bak, “Plant defense against insect herbivores,” International Journal of Molecular Sciences, vol. 14, no. 5, pp. 10242–10297, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. A. R. War, M. G. Paulraj, T. Ahmad et al., “Mechanisms of plant defense against insect herbivores,” Plant Signaling and Behavior, vol. 7, no. 10, pp. 1306–1320, 2012. View at Publisher · View at Google Scholar ·View at Scopus
  6. H. Sanchéz-Sanchéz and A. Morquecho-Contreras, Chemical Plant Defense against Herbivores, InTech, 2017.
  7. A. E. Edris, “Pharmaceutical and therapeutic potentials of essential oils and their individual volatile constituents: a review,” Phytotherapy Research, vol. 21, no. 4, pp. 308–323, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. H.-F. Ji, X.-J. Li, and H.-Y. Zhang, “Natural products and drug discovery,” EMBO Reports, vol. 10, no. 3, pp. 194–200, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. F. Bakkali, S. Averbeck, D. Averbeck, and M. Idaomar, “Biological effects of essential oils—a review,” Food and Chemical Toxicology, vol. 46, no. 2, pp. 446–475, 2008. View at Publisher · View at Google Scholar ·View at Scopus
  10. M. T. Islam, A. M. O. F. da Mata, R. P. S. de Aguiar et al., “Therapeutic Potential of Essential Oils Focusing on Diterpenes,” Phytotherapy Research, pp. 1420–1444, 2016. View at Publisher · View at Google Scholar · View at Scopus
  11. J. Sharifi-Rad, A. Sureda, G. C. Tenore et al., “Biological activities of essential oils: From plant chemoecology to traditional healing systems,” Molecules, vol. 22, no. 1, article no. 70, 2017. View at Publisher · View at Google Scholar · View at Scopus
  12. E. Van de Vel, I. Sampers, and K. Raes, “A review on influencing factors on the minimum inhibitory concentration of essential oils,” Critical Reviews in Food Science and Nutrition, pp. 1–22, 2017. View at Publisher · View at Google Scholar
  13. E. Çetinus, T. Temiz, M. Ergül, A. Altun, Ş. Çetinus, and T. Kaya, “Thyme essential oil inhibits proliferation of DLD-1 colorectal cancer cells through antioxidant effect,” Cumhuriyet Medical Journal, vol. 35, no. 1, pp. 14–24, 2013. View at Publisher · View at Google Scholar
  14. M. M. Suhail, W. Wu, A. Cao et al., “Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells,” BMC Complementary and Alternative Medicine, vol. 11, article no. 129, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. Y. Yang, Y. Yue, Y. Runwei, and Z. Guolin, “Cytotoxic, apoptotic and antioxidant activity of the essential oil of Amomum tsao-ko,” Bioresource Technology, vol. 101, no. 11, pp. 4205–4211, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. A. C. Mesa-Arango, J. Montiel-Ramos, B. Zapata, C. Durán, L. Betancur-Galvis, and E. Stashenko, “Citral and carvone chemotypes from the essential oils of Colombian Lippia alba (Mill.) N.E. brown: composition, cytotoxicity and antifungal activity,” Memórias do Instituto Oswaldo Cruz, vol. 104, no. 6, pp. 878–884, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. M. B. Frank, Q. Yang, J. Osban et al., “Frankincense oil derived from Boswellia carteri induces tumor cell specific cytotoxicity,” BMC Complementary and Alternative Medicine, vol. 9, article no. 6, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. S. L. Da Silva, J. D. S. Chaar, P. D. M. S. Figueiredo, and T. Yano, “Cytotoxic evaluation of essential oil from Casearia sylvestris Sw on human cancer cells and erythrocytes,” Acta Amazonica, vol. 38, no. 1, pp. 107–112, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. S. L. da Silva, P. M. Figueiredo, and T. Yano, “Cytotoxic evaluation of essential oil from Zanthoxylum rhoifolium Lam. leaves,” Acta Amazonica, vol. 37, no. 2, pp. 281–286, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. E. Amiel, R. Ofir, N. Dudai, E. Soloway, T. Rabinsky, and S. Rachmilevitch, “β-Caryophyllene, a compound isolated from the biblical balm of gilead (Commiphora gileadensis), is a selective apoptosis inducer for tumor cell lines,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 872394, 8 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  21. J. Sœur, L. Marrot, P. Perez et al., “Selective cytotoxicity of Aniba rosaeodora essential oil towards epidermoid cancer cells through induction of apoptosis,” Mutation Research – Genetic Toxicology and Environmental Mutagenesis, vol. 718, no. 1-2, pp. 24–32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. T. Rabi and A. Bishayee, “d-Limonene sensitizes docetaxel-induced cytotoxicity in human prostate cancer cells: Generation of reactive oxygen species and induction of apoptosis,” Journal of Carcinogenesis, vol. 8, article no. 9, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. J. Legault and A. Pichette, “Potentiating effect of β-caryophyllene on anticancer activity of α-humulene, isocaryophyllene and paclitaxel,” Journal of Pharmacy and Pharmacology, vol. 59, no. 12, pp. 1643–1647, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Tongnuanchan and S. Benjakul, “Essential oils: extraction, bioactivities, and their uses for food preservation,” Journal of Food Science, vol. 79, no. 7, pp. R1231–R1249, 2014. View at Publisher · View at Google Scholar · View at Scopus
  25. G. Santana-Rios, G. A. Orner, A. Amantana, C. Provost, S.-Y. Wu, and R. H. Dashwood, “Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay,” Mutation Research – Genetic Toxicology and Environmental Mutagenesis, vol. 495, no. 1-2, pp. 61–74, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. A. Astani, J. Reichling, and P. Schnitzler, “Comparative study on the antiviral activity of selected monoterpenes derived from essential oils,” Phytotherapy Research, vol. 24, no. 5, pp. 673–679, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. N. Dias, M. C. Dias, C. Cavaleiro, M. C. Sousa, N. Lima, and M. Machado, “Oxygenated monoterpenes-rich volatile oils as potential antifungal agents for dermatophytes,” Natural Product Research (Formerly Natural Product Letters), vol. 31, no. 4, pp. 460–464, 2017. View at Publisher · View at Google Scholar ·View at Scopus
  28. A. Amin, H. Gali-Muhtasib, and R. Schneider-Stock, “Overview of major classes of plant-derived anti-cancer drugs,” International Journal of Biomedical Science, vol. 5, pp. 1–11, 2009. View at Google Scholar
  29. S. Saljoughian, S. Roohinejad, A. E.-D. A. Bekhit et al., “The effects of food essential oils on cardiovascular diseases: A review,” Critical Reviews in Food Science and Nutrition, pp. 1–18, 2017. View at Publisher · View at Google Scholar · View at Scopus
  30. E. Shayganni, M. Bahmani, S. Asgary, and M. Rafieian-Kopaei, “Inflammaging and cardiovascular disease: Management by medicinal plants,” Phytomedicine, vol. 23, no. 11, pp. 1119–1126, 2016. View at Publisher · View at Google Scholar · View at Scopus
  31. T. U. De Andrade, G. A. Brasil, D. C. Endringer, F. R. Da Nóbrega, and D. P. De Sousa, “Cardiovascular activity of the chemical constituents of essential oils,” Molecules, vol. 22, no. 9, article no. 1539, 2017.View at Publisher · View at Google Scholar · View at Scopus
  32. B. H. Ali and G. Blunden, “Pharmacological and toxicological properties of Nigella sativa,” Phytotherapy Research, vol. 17, no. 4, pp. 299–305, 2003. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Silva, W. Abebe, S. M. Sousa, V. G. Duarte, M. I. L. Machado, and F. J. A. Matos, “Analgesic and anti-inflammatory effects of essential oils of Eucalyptus,” Journal of Ethnopharmacology, vol. 89, no. 2-3, pp. 277–283, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. International Agency for Research on Cancer, Cancer Fact Sheets: All Cancers excluding Non-Melanoma Skin, 2012, http://gco.iarc.fr/today/fact-sheets-cancers?cancer=29&type=0&sex=0.
  35. World Health Organisation, Cancer, 2015, http://www.who.int/mediacentre/factsheets/fs297/en/.
  36. L. R. Ferguson, H. Chen H, and A. R. Collins, “Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition,” Seminars in Cancer Biology, vol. 35, pp. S5–S24, 2015. View at Publisher · View at Google Scholar
  37. P. Fresco, F. Borges, C. Diniz, and M. P. M. Marques, “New insights on the anticancer properties of dietary polyphenols,” Medicinal Research Reviews, vol. 26, no. 6, pp. 747–766, 2006. View at Publisher ·View at Google Scholar · View at Scopus
  38. M. A. Morse and G. D. Stoner, “Cancer chemoprevention: Principles and prospects,” Carcinogenesis, vol. 14, no. 9, pp. 1737–1746, 1993. View at Publisher · View at Google Scholar · View at Scopus
  39. B. A. Weaver, “How Taxol/paclitaxel kills cancer cells,” Molecular Biology of the Cell (MBoC), vol. 25, no. 18, pp. 2677–2681, 2014. View at Publisher · View at Google Scholar · View at Scopus
  40. R. A. Holton, H.-B. Kim, C. Somoza et al., “First total synthesis of taxol. 2. Complication of the C and D rings,” Journal of the American Chemical Society, vol. 116, no. 4, pp. 1599-1600, 1994. View at Publisher ·View at Google Scholar · View at Scopus
  41. O. Altshuler, M. Abu-Abied, D. Chaimovitsh et al., “Enantioselective effects of (+)- and (-)-citronellal on animal and plant microtubules,” Journal of Natural Products, vol. 76, no. 9, pp. 1598–1604, 2013. View at Publisher · View at Google Scholar · View at Scopus
  42. P. Sitarek, P. Rijo, C. Garcia et al., “Antibacterial, Anti-Inflammatory, Antioxidant, and Antiproliferative Properties of Essential Oils from Hairy and Normal Roots of Leonurus sibiricus L. And Their Chemical Composition,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 7384061, 2017. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Kada and K. Shimoi, “Desmutagens and bio-antimutagens—their modes of action,” BioEssays, vol. 7, no. 3, pp. 113–116, 1987. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Ramel, U. K. Alekperov, B. N. Ames, T. Kada, and L. W. Wattenberg, “Inhibitors of mutagenesis and their relevance to carcinogenesis. Report by ICPEMC expert group on antimutagens and desmutagens,” Mutation Research/Reviews in Genetic Toxicology, vol. 168, no. 1, pp. 47–65, 1986. View at Publisher ·View at Google Scholar · View at Scopus
  45. S. De Flora and C. Ramel, “Mechanisms of inhibitors of mutagenesis and carcinogenesis. Classification and overview,” Mutation Research – Fundamental and Molecular Mechanisms of Mutagenesis, vol. 202, no. 2, pp. 285–306, 1988. View at Publisher · View at Google Scholar · View at Scopus
  46. P. Jancova, P. Anzenbacher, and E. Anzenbacherova, “Phase II drug metabolizing enzymes,” Biomedical Papers, vol. 154, no. 2, pp. 103–116, 2010. View at Publisher · View at Google Scholar
  47. V. A. Gudi and S. V. Singh, “Effect of diallyl sulfide, a naturally occurring anti-carcinogen, on glutathione-dependent detoxification enzymes of female CD-1 mouse tissues,” Biochemical Pharmacology, vol. 42, no. 6, pp. 1261–1265, 1991. View at Publisher · View at Google Scholar · View at Scopus
  48. D. Haber, M.-H. Siess, I. De Waziers, P. Beaune, and M. Suschetet, “Modification of hepatic drug-metabolizing enzymes in rat fed naturally occurring allyl sulphides,” Xenobiotica, vol. 24, no. 2, pp. 169–182, 1994. View at Publisher · View at Google Scholar · View at Scopus
  49. N. D. Kim, S. G. Kim, and M. K. Kwak, “Enhanced expression of rat microsomal epoxide hydrolase gene by organosulfur compounds,” Biochemical Pharmacology, vol. 47, no. 3, pp. 541–547, 1994. View at Publisher · View at Google Scholar · View at Scopus
  50. V. L. Sparnins, G. Barany, and L. W. Wattenberg, “Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione s-transferase activity in the mouse,” Carcinogenesis, vol. 9, no. 1, pp. 131–134, 1988. View at Publisher · View at Google Scholar · View at Scopus
  51. F. Peter Guengerich, “Metabolic activation of carcinogens,” Pharmacology & Therapeutics, vol. 54, no. 1, pp. 17–61, 1992. View at Publisher · View at Google Scholar · View at Scopus
  52. L. Wattenberg, “Inhibition of carcinogenesis by minor dietary constituents,” Cancer Research, vol. 52, no. 7, pp. 2085–2091, 1992. View at Google Scholar
  53. Y. Nakamura, M. Miyamoto, A. Murakami, H. Ohigashi, T. Osawa, and K. Uchida, “A phase II detoxification enzyme inducer from lemongrass: Identification of citral and involvement of electrophilic reaction in the enzyme induction,” Biochemical and Biophysical Research Communications, vol. 302, no. 3, pp. 593–600, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Kapur, M. Felder, L. Fass et al., “Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation,” Scientific Reports, vol. 6, Article ID 27530, 2016. View at Publisher · View at Google Scholar · View at Scopus
  55. L. J. Sanches, P. C. Marinello, C. Panis et al., “Cytotoxicity of citral against melanoma cells: The involvement of oxidative stress generation and cell growth protein reduction,” Tumor Biology, vol. 39, no. 3, 2017. View at Publisher · View at Google Scholar · View at Scopus
  56. N. Girola, C. R. Figueiredo, C. F. Farias et al., “Camphene isolated from essential oil of Piper cernuum(Piperaceae) induces intrinsic apoptosis in melanoma cells and displays antitumor activity in vivo,” Biochemical and Biophysical Research Communications, vol. 467, no. 4, pp. 928–934, 2015. View at Publisher · View at Google Scholar · View at Scopus
  57. K. M. Arunasree, “Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231,” Phytomedicine, vol. 17, no. 8-9, pp. 581–588, 2010. View at Publisher · View at Google Scholar
  58. N. Dudai, Y. Weinstein, M. Krup, T. Rabinski, and R. Ofir, “Citral is a new inducer of caspase-3 in tumor cell lines,” Planta Medica, vol. 71, no. 5, pp. 484–488, 2005. View at Publisher · View at Google Scholar ·View at Scopus
  59. R. M. Queiroz, C. M. Takiya, and L. P. Guimaraes, “Apoptosis-inducing effects of Melissa officinalis L. essential oil in glioblastoma multiforme cells,” Cancer Investigation, vol. 32, no. 6, pp. 226–235, 2014.View at Publisher · View at Google Scholar
  60. B. Y. Sheikh, M. M. R. Sarker, M. N. A. Kamarudin, and G. Mohan, “Antiproliferative and apoptosis inducing effects of citral via p53 and ROS-induced mitochondrial-mediated apoptosis in human colorectal HCT116 and HT29 cell lines,” Biomedicine & Pharmacotherapy, vol. 96, pp. 834–846, 2017.View at Google Scholar
  61. M. L. Thomas, R. de Antueno, K. M. Coyle et al., “Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3,” Molecular Oncology, vol. 10, no. 9, pp. 1485–1496, 2016. View at Publisher · View at Google Scholar · View at Scopus
  62. F. Naz, F. I. Khan, T. Mohammad et al., “Investigation of molecular mechanism of recognition between citral and MARK4: A newer therapeutic approach to attenuate cancer cell progression,” International Journal of Biological Macromolecules, vol. 107, pp. 2580–2589, 2018. View at Publisher · View at Google Scholar
  63. E. Fayard, L. A. Tintignac, A. Baudry, and B. A. Hemmings, “Protein kinase B/Akt at a glance,” Journal of Cell Science, vol. 118, no. 24, pp. 5675–5678, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Seal, P. Chatterjee, S. Bhattacharya et al., “Vapor of Volatile Oils from Litsea cubeba Seed Induces Apoptosis and Causes Cell Cycle Arrest in Lung Cancer Cells,” PLoS ONE, vol. 7, no. 10, Article ID e47014, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. C.-C. Wu, J. G. Chung, S.-J. Tsai, J. H. Yang, and L. Y. Sheen, “Differential effects of allyl sulfides from garlic essential oil on cell cycle regulation in human liver tumor cells,” Food and Chemical Toxicology, vol. 42, no. 12, pp. 1937–1947, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. B. Hoesel and J. A. Schmid, “The complexity of NF-κB signaling in inflammation and cancer,” Molecular Cancer, vol. 12, no. 1, article 86, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. N. Dehne, J. Mora, D. Namgaladze, A. Weigert, and B. Brüne, “Cancer cell and macrophage cross-talk in the tumor microenvironment,” Current Opinion in Pharmacology, vol. 35, pp. 12–19, 2017. View at Publisher · View at Google Scholar · View at Scopus
  68. Y. Ben-Neriah and M. Karin, “Inflammation meets cancer, with NF-κB as the matchmaker,” Nature Immunology, vol. 12, no. 8, pp. 715–723, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. S. B. Hassan, H. Muhtasib, H. Goransson, and R. Larsson, “Alpha Terpineol: A Potential Anti-cancer Agent which Acts through Suppressing NF-κB Signalling,” Anti Cancer Research, vol. 30, no. 6, pp. 1911–1919, 2010. View at Google Scholar
  70. S. J. Deeb, Enhancement of cell death by linalyl acetate and [alpha]-terpineol through targeting the nuclear factor-[kappa] B activation pathway in human colon cancer cells, American University of Beirut, 2000.
  71. B. van Houten, V. Woshner, and J. H. Santos, “Role of mitochondrial DNA in toxic responses to oxidative stress,” DNA Repair, vol. 5, no. 2, pp. 145–152, 2006. View at Publisher · View at Google Scholar · View at Scopus
  72. E. Fitsiou, I. Anestopoulos, K. Chlichlia et al., “Antioxidant and antiproliferative properties of the essential oils of Satureja thymbra and Satureja parnassica and their major constituents,” Anticancer Reseach, vol. 36, no. 11, pp. 5757–5763, 2016. View at Publisher · View at Google Scholar · View at Scopus
  73. D. R. Merchán Arenas, A. M. Acevedo, L. Y. Vargas Méndez, and V. V. Kouznetsov, “Scavenger activity evaluation of the clove bud essential oil (Eugenia caryophyllus) and eugenol derivatives employing ABTS +• decolorization,” Scientia Pharmaceutica, vol. 79, no. 4, pp. 779–791, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. A. Manjamalai and V. M. Berlin Grace, “Antioxidant activity of essential oils from wedelia chinensis (osbeck) in vitro and in vivo lung cancer bearing C57BL/6 mice,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 7, pp. 3065–3071, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. K. Le Gal, M. X. Ibrahim, C. Wiel et al., “Antioxidants can increase melanoma metastasis in mice,” Science Translational Medicine, vol. 7, no. 308, Article ID 308re8, 2015. View at Publisher · View at Google Scholar · View at Scopus
  76. D. C. Phillips, K. J. Woollard, and H. R. Griffiths, “The anti-inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species,” British Journal of Pharmacology, vol. 138, no. 3, pp. 501–511, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. J. Legault, W. Dahl, E. Debiton, A. Pichette, and J.-C. Madelmont, “Antitumor activity of balsam fir oil: Production of reactive oxygen species induced by α-humulene as possible mechanism of action,” Planta Medica, vol. 69, no. 5, pp. 402–407, 2003. View at Publisher · View at Google Scholar · View at Scopus
  78. S.-S. Feng and S. Chien, “Chemotherapeutic engineering: Application and further development of chemical engineering principles for chemotherapy of cancer and other diseases,” Chemical Engineering Science, vol. 58, no. 18, pp. 4087–4114, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. R. V. J. Chari, “Targeted cancer therapy: Conferring specificity to cytotoxic drugs,” Accounts of Chemical Research, vol. 41, no. 1, pp. 98–107, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. X. Ni, M. M. Suhail, Q. Yang et al., “Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model,” BMC Complementary and Alternative Medicine, vol. 12, article no. 253, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. M. B. Lustberg, “Management of neutropenia in cancer patients,” Clinical Advances in Hematology & Oncology, vol. 10, no. 12, pp. 825-826, 2012. View at Google Scholar
  82. S. Zhuang, S. Chen, J. Tsai et al., “Effect of citronellol and the Chinese medical herb complex on cellular immunity of cancer patients receiving chemotherapy/radiotherapy,” Phytotherapy Research, vol. 23, no. 6, pp. 785–790, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Carnesecchi, R. Bras-Gonçalves, A. Bradaia et al., “Geraniol, a component of plant essential oils, modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human colon tumor xenografts,” Cancer Letters, vol. 215, no. 1, pp. 53–59, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. S. Carnesecchi, K. Langley, F. Exinger, F. Gosse, and F. Raul, “Geraniol, a component of plant essential oils, sensitizes human colonic cancer cells to 5-fluorouracil treatment,” The Journal of Pharmacology and Experimental Therapeutics, vol. 301, no. 2, pp. 625–630, 2002. View at Publisher · View at Google Scholar· View at Scopus
  85. A. Vieira, R. Heidor, M. T. Cardozo et al., “Efficacy of geraniol but not of β-ionone or their combination for the chemoprevention of rat colon carcinogenesis,” Brazilian Journal of Medical and Biological Research, vol. 44, no. 6, pp. 538–545, 2011. View at Publisher · View at Google Scholar · View at Scopus
  86. M. S. Rajput and P. Agrawal, “Microspheres in cancer therapy,” Indian Journal of Cancer, vol. 47, no. 4, pp. 458–468, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. V. S. Periasamy, J. Athinarayanan, and A. A. Alshatwi, “Anticancer activity of an ultrasonic nanoemulsion formulation of Nigella sativa L. essential oil on human breast cancer cells,” Ultrasonics Sonochemistry, vol. 31, pp. 449–455, 2016. View at Publisher · View at Google Scholar · View at Scopus
  88. T. Sun, Y. S. Zhang, B. Pang, D. C. Hyun, M. Yang, and Y. Xia, “Engineered nanoparticles for drug delivery in cancer therapy,” Angewandte Chemie International Edition, vol. 53, no. 46, pp. 12320–12364, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. A. R. Bilia, C. Guccione, B. Isacchi, C. Righeschi, F. Firenzuoli, and M. C. Bergonzi, “Essential oils loaded in nanosystems: a developing strategy for a successful therapeutic approach,” Evidence-Based Complementary and Alternative Medicine, vol. 2014, Article ID 651593, 14 pages, 2014. View at Publisher· View at Google Scholar