Anti Cancer Supplements

1. Integrative Medicines:

Integrative medicine constitutes natural products involving herbs, botanicals, and mind and body practices, which is a part of the integrative approach. The approach of using integrative medicines among cancer patients has involved several medical clinics and cancer centers in fulfilling the demand of the patients. Patients often use the integrative medicines as per their own will, without any discussion regarding their use with an oncologist, which can be dangerous, especially for oncology patients, who are particularly frail and may require modified integrative treatments. The oncologist further recommends integrative medicine to determine the patient’s cancer journey. Certain herbs and supplements in integrative medicines interfere with chemotherapy drugs, making them less effective. Hence, considering this, the healthcare professional offers appropriate patient care. 

Many cancer patients use integrative medicines that show efficacy in prevention and treatment, boost the immune system, improve well-being, and reduce the symptoms of either the disease or disease treatment, such as nausea, insomnia, and pain cancer. Its intake, as the healthcare professional recommends, helps improve the quality of life of cancer patients during chemotherapy instead of increasing the therapeutic efficacy. Also, emotional distress, depression, insomnia, nausea, loss of appetite, and other symptoms resulting from disease or treatment are mitigated by adhering to the use of integrative medicines. Integrative medicines include some non-biological therapies such as meditation, deep breathing, or acupuncture that show no risk of drug interactions and are further advisable for cancer patients.

Integrative medicines provide several benefits that improve the patients’ health outcomes. Most patients tend to respond to herbal supplements with the effect of reducing and terminating their symptoms. The patients often undergo conventional medications as soon as their diagnosis is made. Therefore, integrating integrative treatments are carried out alongside the traditional medical approaches. It reduces the symptoms, controls the disease progression, and effectively improves patients’ symptoms by lowering their cortisone and analgesic usage, thus enhancing their quality of life. It integrates the use of plants, evolving more decisive action on the body when compared with food and spices. It constitutes different herbal combinations showing excellent results in patients’ health outcomes. The ayurvedic plants are often safe and free from side effects but sometimes may show some variations in the efficacy. Some undesirable effects due to the inappropriate use of herbs have been reported in some cases. Integrative medicines have demonstrated less toxicity and good acceptability among patients suffering from different illnesses, mainly caused by reduced immune responses. The well-being of the patients, which is hindered due to chemotherapy toxicities, is improved by combining the integrated medicines. In cases where biomedical treatment in cancer does not show efficacy, the amalgamation of these medicinal approaches effectively strengthens digestion, eliminates toxins, reduces tumor growth, and improves tissue metabolism. 

Integrative medicines help enhance an individual’s physical and emotional health by incorporating additional evidence with informed protocols and conventional therapy. Five domain concepts have been introduced that involve manipulative & body-based methods, mind-body medicine, alternative medical systems, energy therapies, and biologically based therapies. Cancer survivors choose integrative medicine to manage long-term adverse effects and symptoms and improve their quality of life.

Some of the integrative medicines with natural products constituents are illustrated below:

1.1 Medical Cannabis:

Medical Cannabis or medical marijuana is a plant either in a raw or dried form or an extract or preparation made from Cannabis Sativa or Cannabis Indica for medical use prescribed by physicians for their patients. Cannabinoids are found naturally in Cannabis. The Cannabis plant has been used for centuries around the world. Medical Cannabis helps relieve pain and reduce nausea and vomiting for chemo-induced patients. Medical Cannabis also decreases the number of seizures in rare forms of epilepsy (Bridgeman & Abazia, 2017). Studies in laboratories done on animal models suggest that cannabinoids can kill cancer cells. The study indicates that patients who consume medicated Cannabis experience less nausea than those on antiemetics or placebo (Parker et al., 2011). They might face some side effects such as feeling high and a certain amount of dizziness.

Working against cancer growth or preventing its spread improves the chances of survival with the help of treatments and therapies to improve the anti-cancer action. As per current research, there is no evidence that Medical Cannabis is the cure for cancer. Cannabinoids like CBD and others have exhibited anti-cancer properties. The details are represented below:

• Cannabinoids have reduced breast tumor growth, promoted the death of cancer-producing cells, and reduced the levels of metastasis and angiogenesis (blood vessel growth to supply tumors) in animal studies (Dariš et al., 2019).
• Animal research on rats has shown that Cannabinoids have inhibited growth and led to the death of thyroid cells (Hinz & Ramer, 2019).
• The IL-1 _р secretion and metastasis have drastically reduced in Ovarian Cancer Cells.
• The precursor of CBD, which is CBDA, has inhibited the migration of cancer cells.
• Chemo prevention was observed in Colon Cancer (Zaiachuk et al., 2021).
• An anti-evasive action was observed in the Lung Cancer cells (CBD) (Ramer et al., 2012).

Many results show a positive impact of Medical Cannabis, whereas other studies find a contradiction. For example, in 2013, breast, prostate, glioma, lymphoma, and pancreatic cancer cell studies showed a positive efficacy. Whereas in 2018, studies showed insufficient evidence to prove that Medical Cannabis can cure cancer. Thereby, further research is needed for any such conclusions to be drawn to conclude the anti-cancer role of Cannabinoids. 

The use of Medical Cannabis in cancer patients has been illustrated below:

• Pain: Clinical studies show that a patient can relieve the pain associated with neuropathy, fibromyalgia, and rheumatoid arthritis by consuming Cannabis.
• Glaucoma: According to the current studies, it is not recommended to consume Cannabis for glaucoma as it can be harmful.
• Spasticity: Cannabinoids have reduced spasticity in patients.
• Chemotherapy-induced nausea and vomiting: The sensation of nausea and vomiting due to chemotherapy is reduced by Cannabis.
• Sleep: There is currently no evidence to prove that Cannabis is helpful for sleep disorders.
• Appetite stimulant: There is currently no evidence to prove that Cannabis is helpful as an appetite stimulant.
• Cancer treatment:Studies have shown that Cannabis is not the cure for cancer but can certainly reduce its pain.
• Epilepsy: The consumption of CBD reduces the number of seizures a patient faces.
• Use with children: Only a few studies have been conducted using Medical Cannabis and Cannabinoids in adolescents and children.

1.2 Curcumin: 

The genus of Curcuma has evolved medicinal applications consisting of almost a constitution of 120 species. Among all the curcumin species, Curcuma longa L. is the most identified species, a cultivated plant grown in a warm climate in many regions of the world (Wu, 2015). The taxonomic identity of the genus is complicated because of its brief period of flowering and herbarium preparation due to the flashiness of tubers, rhizomes, and inflorescence. The most commonly used plant part for this plant species is the rhizomes which consist of various compounds involving bioactive non-volatile curcuminoids (curcumin, dimethoxy-, and bisdemethoxy-curcumin) and the compounds present in volatile oil (mono and sesquiterpenoids) (Lobo et al., 2009). 

Curcumin is known to have antioxidant, anti-inflammatory, and anti-cancer effects. These effects have played an essential role in preventing and treating various illnesses ranging from cancer to autoimmune, neurological, cardiovascular diseases, and diabetes. Furthermore, it is aimed to increase the biological activity and physiological effects of curcumin on the body by synthesizing curcumin analogues. Curcumin is considered an essential therapeutic agent and is currently being tested for the human trials to determine different conditions such as myeloma, pancreatic cancer, colon cancer, mastitis myelodysplastic syndromes, psoriasis, Alzheimer’s disease, diabetic nephropathy, periodontal disease, oral cancers, recurrent aphthous stomatitis, precancerous lesion and conditions. Preliminary findings from many small and uncontrolled studies indicate that curcumin is effective in treating cancer.

• Colorectal Cancer: The clinical results of curcumin administration in patients with colorectal cancer results in sufficient curcumin concentrations that persist in colonic mucosa. Higher curcumin exposure achieved by several newer formulations has shown important implications for the optimal treatment of cancers other than those in the gastrointestinal tract (Adiwidjaja et al., 2017).
• Pancreatic Cancer: Higher survival rates have been observed among patients with gemcitabine-resistant pancreatic cancer compared to gemcitabine alone (Kanai et al., 2011). Oral curcumin is well tolerated and, despite its limited absorption, shows biological activity in patients with pancreatic cancer (Dhillon et al., 2008).
• Anti-cancer effects of Curcumin: Curcumin is reported against several different types of cancer, including prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, and head and neck cancer, both in vitro and in vivo. 
• Multiple myeloma: The clinical trial of curcumin shows the potential to slow the disease process in patients suffering from multiple myeloma (Golombick et al., 2012).

1.3 Melatonin: 

It is the hormone produced by the pineal gland within the brain. It helps in regulating sleep and wake cycles. Melatonin is found in fruits, nuts, olive oil and wine. It is also available as a supplement used as a sleep aid. The cancer is aggressive among patients who have nighttime production of Melatonin. The supplementation of Melatonin in cancer patients shows anti-cancer effects. Melatonin is used as an adjuvant to establish improved outcomes and responses to conventional treatments in cancer. It has improved the quality of life among cancer patients by reducing side effects and symptoms. The measurement of melatonin concentration in blood and urine is associated with cancer risk. Reduced risk of cancer has been observed with melatonin supplementation (Li et al., 2017).

The clinical evidence for Melatonin is illustrated below:

• Studies have revealed that administration of Melatonin in combination with tamoxifen in women with breast cancer showed progression (González-González et al., 2018). The simultaneous administration of Melatonin and tamoxifen evolved cancer regression in women with metastatic breast cancer that did not respond to tamoxifen alone. 
• The parallel administration of Melatonin with interleukin 2 in patients suffering from distant metastases of non-small cell lung carcinoma, liver carcinoma, bowel carcinoma, stomach carcinoma, pancreatic carcinoma and breast cancer results in cancer regression and disease stabilization (Gurunathan et al., 2021). 
• Melatonin inhibits the growth of breast cancer cells, cervical cancer cells and ovarian cancer cells. It is a group of regulatory factors that controls cell multiplication and death (Shen et al., 2016).
• When used with chemotherapy and radiotherapy, increased survival rates have been observed in people with skin cancer (Pourhanifeh et al., 2019).

1.4 Silymarin Milk Thistle:

Silymarin is a natural remedy effective in treating hepatitis and cirrhosis while protecting the liver against some toxic substances. Silybum marianum is a herbal species used for centuries as a herbal treatment for several disorders. It possesses antioxidant, lipid‐lowering, antihypertensive, antidiabetic, antiatherosclerotic, anti‐obesity, and hepatoprotective effects. Milk thistle (Silybum marianum) is an ancient medicinal plant used for centuries to treat different diseases, mainly liver and gallbladder disorders, protecting the liver against snake bites and insect stings, and mushroom poisoning and alcohol abuse.

Its application has been studied by conducting both in vivo and in vitro studies, mainly showing efficacy in cancer. It is considered a chemopreventive agent against various cancer types. Its anti-cancer effects are implicated by the modulation of specific proteins that show anti-inflammatory and anti-metastatic activities. The possible anti-cancer mechanism of Silymarin includes anti-inflammation, cell regulation, apoptosis induction, inhibition of angiogenesis, inhibition of invasion and metastasis, and growth inhibition. Some of the clinical evidence of Silymarin milk thistle has been discussed below:

• Hepatoprotective effects of milk thistle are observed among the patients undergoing chemotherapy which is most often toxic to the liver (Siegel & Stebbing, 2013).
• Children undergoing chemotherapy for acute leukemia recommended that milk thistle is effective in improving the liver function in children. However, there was a trend toward greater chemotherapy doses in those who received milk thistle (Ladas et al., 2010).
• Other studies have also revealed that the patients undergoing chemotherapy have shown an increased concentration of liver enzymes during treatment for leukaemias which was improved by administering milk thistle (Ramasamy & Agarwal, 2008).
• Milk thistle compounds have shown anti-cancer effects in preclinical models, mainly involving induction of apoptosis in the case of colon cancer cells that causes senescence of cancer cells in a mouse model of breast cancer and shows blocking of angiogenesis in prostate cancer models (Deep & Agarwal, 2010). 
• The compounds of milk thistle have shown prevention from the development of skin cancers when carried out on the skin of mice exposed to ultraviolet radiation (Prasad et al., 2020).

1.5 Reishi Mushroom

Reishi Mushroom is obtained from traditional Chinese medicine, and Ganoderma Lucidum is a species of reishi mushroom. It effectively extends the individual’s life and promotes health benefits. It shows efficacy in preventing and treating many diseases and exerts anti-cancer properties. It benefits cancer patients and is most often used in drug development after testing its reliability. It is usually recommended as an immune system support supplement in cancer treatment. The clinical evidence and preclinical trials of the reishi mushroom have shown promising results of its antitumor activity. It can stimulate host immune functions by considerably increasing CD3, CD4 and CD8 lymphocyte percentages. Some of the clinical evidence are discussed below:

• Administration of reishi mushroom in lung cancer patients has shown improved tumor response (Liu et al., 2020).
• When taken in the form of drugs, reishi mushroom helps reduce cell viability in human colon cancer cells (Liang et al., 2014).
• It inhibits prostate cancer-dependent angiogenesis and has been considered a potential therapeutic use for the treatment of prostate cancer (Stanley et al., 2005).
• It inhibits the invasion of breast and prostate cancer cells by a common mechanism and could have potential therapeutic use for cancer treatment (Sliva et al., 2002).

1.6 Vitamin D3:

Vitamin D is a fat-soluble vitamin produced by the body when the skin is exposed to ultraviolet rays in sunlight. It is found naturally in some food items such as egg yolks, cod liver oil, fish oil, wild fish such as salmon, sardines, herring and cod, blood sausage, organ meats such as liver, butter, and mushrooms that have been exposed to sunlight. Also, vitamin D is found in some dairy products, orange juice, soy milk and cereals and is primarily available as a dietary supplement. Vitamin D intake works against cancer growth or spread, improving survival, or working with other treatments or therapies to enhance their anti-cancer action. Some of the clinical evidence are discussed below:

• The high vitamin D serum levels have decreased the death rate among breast cancer patients (Maalmi et al., 2014).
• Better prognosis with medium or high vitamin D serum levels is evaluated compared with low levels, with a more substantial effect in patients receiving hormone therapy (Tretli et al., 2009).
• Supplementation of vitamin D shows cell-killing (cytotoxic) effects of docetaxel which is used in treating breast, lung, prostate, stomach, and head and neck cancers (Frenkel & Gupta, 2010).
• Regression and improved metabolic status is observed in cervical intraepithelial neoplasia grade 1 (Vahedpoor et al., 2017). 
• Reduction in the progression of low-grade prostate cancer in pilot studies has been evaluated (Ahn et al., 2016).

1.7 Essential Oils:

Essential oils are complex mixtures of low molecular weight compounds extracted from plants. The main constituents of essential oils include terpenes and phenylpropanoids, which possess biological and pharmaceutical properties showing insecticidal, parasiticidal, antimicrobial, antioxidant, anti-inflammatory, analgesic, antinociceptive, anticarcinogenic, and antitumor properties. Essential oils are obtained from aromatic plants’ secondary metabolites possessing different functions. It acts as a defense against herbivores, insects, and microorganisms, maintains communication with plants of the same species and helps to signal within the plant in response to environmental stimuli. These have been effective in treating diseases involving emetics and laxatives, muscle relaxants, cardiac stimulants, and cardiac depressants resulting in hypotension and induction of bradycardia. 

Essential oils have been used as dietary supplements. It acts as an anti-cancer therapeutic agent that helps cancer prevention while establishing tumor cells and interacting with the microenvironment. Some of the clinical evidence of essential oils are discussed below:

• The essential oils are used as complementary and alternative medicine among patients with colorectal cancer (Tough et al., 2002).
• It shows anti-proliferative effects on human metastatic breast cancer cell lines (Arunasree, 2010). 
• The constituents of essential oils induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells (Priyadarsini et al., 2010).

1.8 Grapeseed

Grape seed extracts are obtained from seeds of grapes (Vitis vinifera) which is the by-product of the grape juice. It is used as a healthy dietary supplement in capsule or tablet formulations containing 100–500 mg. It consists of several polyphenolic components with proanthocyanidins as the principal constituent. Proanthocyanidins consist of pharmacological properties of grape seeds.

Different preclinical studies have been carried out using in vitro approaches and in vivo analyses in animal models that show the protective effects of grape seed extract and its active constituents grape seed proanthocyanidins against skin, breast, prostate, head and neck and lung cancer. The grape seed constituents possess antioxidant and anti-inflammatory properties. Different clinical studies have represented multiple molecular targets affected by treatment with grapeseed extract. Some of them are described below:

• Dietary feeding of proanthocyanidins extracted from grape seeds protects skin from the adverse biological effects of solar ultraviolet (UV) radiation and prevents skin cancer (Mittal et al., 2003).
• Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells (Mantena et al., 2006).
• The grapeseed extract provides efficacy in the chemoprevention of prostate cancer to control this malignancy (Raina et al., 2007).
• 50% survival rate of head and neck squamous cell carcinoma (HNSCC) has represented an improvement due to the chemotherapeutic effect of proanthocyanidins on HNSCC cells (Prasad et al., 2012).
• Grape seed extract efficacy is observed during chemotherapy in non-small cell lung cancer that results in proliferation, apoptosis, and expression of receptors.

1.9 Green tea extract

Tea is the most common beverage consumed across the globe. The plant Camellia Sinensis is used to produce tea that can be classified as green, black and oolong tea, and drinking habits show variations cross-culturally. C Sinensis contains polyphenols, one subgroup being catechins, also known as green tea extracts. Catechins are potent antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Green tea contains four main tea catechins involving 10%-15% epigallocatechin gallate (EGCG), 6%-10% epigallocatechin (EGC), 2%-3% epicatechin gallate (ECG), and 2% epicatechin (EC). 

Several preclinical studies of green tea and its components have been reported to represent efficacy for the growth inhibition of tumors with fewer adverse events. Several clinical studies regarding the green tea extract show efficacy in cancer treatment, mainly involving breast cancer, colorectal cancer, prostate cancer, ovarian cancer, liver cancer, lung cancer, lymphoma, gastric cancer, and pancreatic cancer. Some of them are discussed below:

•  Supplementation with Brazil nuts and green tea extract has shown efficacy in regulating targeted biomarkers concerning colorectal cancer risk in humans (Hu et al., 2016).
• The randomized, placebo-controlled, double-blinded trial investigated the efficacy of green tea extract as a biomarker by evaluating its daily consumption for 12 months in patients with breast cancers (Samavat et al., 2015).
• Daily intake of a standardized, decaffeinated catechin mixture accumulates in the plasma, and its dose is well tolerated among the patients showing a reduction in the likelihood of prostate cancer in men (Kumar et al., 2015).
• Green tea consumption has shown efficacy in chemoprevention among individuals with a high risk of liver cancer (Luo et al., 2006).

1.10 Ayurveda:

Ayurveda integrates three entire states within an individual: physical (including physiological), and mental. Ayurveda is identified as the most formal healthcare system in the country. It provides several benefits that improve the patients’ health outcomes. Most patients tend to respond to ayurvedic treatments with the effect of reducing and terminating their symptoms. The patients often undergo conventional medications as soon as their diagnosis is made. Therefore, integrating ayurvedic therapies is carried out alongside the conventional medical approaches. It reduces the symptoms, controls the disease progression, and effectively improves patients’ symptoms by lowering their cortisone and analgesic usage, thus enhancing their quality of life.

The Ayurveda has integrated the use of plants, evolving more decisive action on the body when compared with food and spices. It constitutes different herbal combinations showing excellent results in patients’ health outcomes. The ayurvedic plants are often safe and free from side effects but sometimes may show some variations in the efficacy. Some undesirable effects due to the inappropriate use of ayurvedic herbs have been reported in some cases. Ayurveda has demonstrated less toxicity and good acceptability among patients suffering from different illnesses, mainly caused by reduced immune responses (Artherholt & Fann, 2012). The well-being of the patients, which is hindered due to chemotherapy toxicities, is improved by integrating the use of Ayurveda (Vyas et al., 2010). In cases where biomedical treatment in cancer does not show any efficacy, integrating the ayurvedic approach effectively strengthens digestion, eliminates toxins, reduces tumor growth, and improves tissue metabolism. 

• AyurZen: AyurZen focuses on bringing the goodness of Ayurvedic medicines to cancer patients. Ayurveda originated in the ancient period of Indian medicine and has been recognized as an effective means of treatment through the centuries. It has been used as an anti-cancer remedy due to its in-built antioxidant and anti-inflammatory properties. AyurZen capsules are a pure blend of selected herbal flowers, roots, fruits and seeds. It is tolerated very well and is known to be an effective drug for prolonged use without adverse effects on health. It is supplemented with other anti-cancer remedies showing synergetic results while attacking only the cancer cells without causing harm to the other body tissues. The nutritional contents of AyurZen include a combination of ten different types of herbs with medicinal properties. The herbs possess specific therapeutic properties, which are used in the preparation of AyurZen while showing effectiveness in health outcomes. The ten essential herbs of AyurZen include Catharanthus alba (Flower), Curcuma longa (Root), Ganoderma lucidum (Biomass), Glycine max (Seed), Moringa oleifera (Fruits), Nigella sativa (Seed), Picrorhiza kurroa (Root), Piper cubeba (Seed), Tribulus Terrestris (Fruit), and Withania somnifera (Root). The clinical outcome of the herbs used in AyurZen preparation is discussed below:

• Catharanthus alba: The anti-cancer alkaloids Vinblastine and Vincristine are derived from the stem and leaf of Catharanthus roseus. These alkaloids show a growth inhibition effect on some human tumors. Experiments have been conducted for Vinblastine that shows efficacy in treating hodgkin’s disease and choriocarcinoma. Vincristine shows effectiveness in treating leukemia in children. Different percentages of the methanolic crude extracts of Catharanthus showed significant anti-cancer activity against numerous cell types in the in vitro condition. The most significant activity was found against the multidrug-resistant tumor types. The antioxidant properties of Catharanthus alba are derived using different assay systems such as Hydroxyl radical-scavenging activity, superoxide radical-scavenging activity, DPPH radical scavenging activity and nitric oxide radical inhibition method. The result represented that the ethanolic extract of the roots of Periwinkle varieties has adhered to the good scavenging effect in the complete essay in a concentration-dependent manner (Bhutkar & Bhise, 2011). 
• Curcuma longa: It is a natural anti-inflammatory agent which helps in reducing inflammation. It also acts as a potent antioxidant that helps boost the immune system response while preventing disease. It is used to prepare medicines showing effectiveness in complementary treatment for cancer. Several studies have been conducted to show clinical characteristics of Curcuma longa through clinical trials showing efficacy in cancer treatment are represented below:

Duration of study	Dosage of the drug	Number of patients	Country	Results	References
N.A	500 mg with soy lecithin	80	Italy	Curcumin reduced side effects	Belcaro et al., (2014)
16 months	500 to 600 mg	10	France	Lowered the concentration of the CEA marker tumor	Bayet-robert et al., (2010)
11 months	8 g	22	Japan	Increased patient survival	Kanai et al., (2011)
10–30 days	1.08 g per day	126	China	Improved the overall health of patients with colorectal cancer	He et al., (2010)
N.A	8 g per day	25	USA	Well-tolerated, limited absorption, and showed activity in some patients	Dhillon et al., (2008)
291 days	2 g per day	24	UK	Curcumin was a safe and tolerable adjunct to FOLFOX chemotherapy in patients with metastatic colorectal cancer	Lynne M Howells et al., (2019)

• Ganoderma lucidum: It is commonly known as Reishi, one of the primary herbs of choice in any immune deficiency disease. They act as immunostimulants along with anti-inflammatory agents while constituting anti-allergenic properties. It contains more than 100 oxygenated triterpenes, most of which are responsible for affecting the activities of NK cells. Laboratory research and preclinical trials have revealed that G. lucidum possesses anticancer and immunomodulatory properties. Its clinical effects have shown efficacy in long-term survival, tumor response, host immune functions and improving quality of life of cancer patients. Randomized control trials have evaluated the effectiveness of G. lucidum medications compared with active or placebo control in cancer patients. A preliminary study using transverse aortic constriction (TAC) was conducted in mice to show anti-cancer and cardioprotective activity (Xie et al., 2016). Its result showed normalized ejection fraction, corrected the fractional shortening generated by TAC, and reduced left ventricular hypertrophy; analysis of total RNA expression revealed the reduced expression of genes associated with cardiac failure and decreasing levels of RNA circ-Foxo3. 
• Glycine max: The soybean seeds are drought-tolerant, nitrogen-fixing plants enriched within the soil. It possesses cosmeceutical and dermatological benefits involving inflammatory, collagen-stimulating effect, potent anti-oxidant scavenging peroxyl radicals, skin lightening effect and protection against UV radiation. The clinical trial for evaluating the efficacy of Glycine max in cancer patients included using human cancer cell lines, which were treated with different concentrations of soybean and transfected with the plasmids (Wang et al., 2018). The growth rate was measured using xCELLigence real-time cell analysis. Quantitative reverse transcription-polymerase chain reaction and Western blot was used to measure the growth rate. The results showed significant inhibitory effects on the growth rates of human cancer cell lines in a concentration-dependent manner. Soybean inhibited the growth rate when the plasmid gene transfected them. 
• Moringa oleifera: It consists of antifungal, antiviral, antidepressant, and anti-inflammatory properties. Testing has been done for extracts from the Moringa oleifera against hepatocarcinoma HepG2, breast MCF7, and colorectal HCT 116/ Caco-2 cells in vitro (Abd-Rabou et al., 2017). Nano-composites are prepared and characterized, and screened on different propagated cancer cell lines. The underlying cytotoxic impact has been followed using apoptosis measurements. The results revealed that all extracts kill the different cancer cells. Hence,  Moringa oleifera can be used as a natural source of anti-cancer compounds. Another clinical trial demonstrated the efficacy of anti-cancer activity of Moringa oleifera extracts in human hepatocellular carcinoma HepG2 cells (Jung et al., 2015). Hollow fiber assay is carried out for oral administration of the extract that reduces the proliferation of the HepG2 cells. Hence, this clinical trial depicts the efficacy of Moringa oleifera when administered orally for treating liver and lung cancer.
• Nigella sativa: It is known as the black seed that is effective in boosting the immune system, fighting cancer, preventing pregnancy, reducing swelling, and reducing allergic reactions while acting as an antihistamine. Some of the clinical trials of Nigella sativa are discussed in below table:

Cancer model	Cancer cells	Intervention	Results	References
In vitro studies	Doxorubicin-resistanthuman breast cancer cells line (MCF-7/DOX cells)	Thymoquinone  (25, 50 or 100 µM) for 48 hours & NSO Nano emulsion	Induces apoptosis, p53 protein showing concentration dependent growth inhibition	Arafa et al., (2011)
Human cervical squamouscancer cells	Thymoquinone  (25, 50 or 100 µM) for 48 hours & NSO Nano emulsion	less cytotoxic towards normal cells	Arafa et al., (2011)
In vivo studies	Diethylnitrosamine induced hepatocarcinogenesis in Wistar rats	Ethanolic extract of NS (250 mg/kg) for 5 consecutive days	Induced increment of liver weight, hepato-somatic indices, serum AFP and VEGF levels, and hepatic HGFβ protein expression being reversed by the extract.	Shahin et al., (2018)
Rat multi-organcarcinogenesis	NSO for 30 weeks	Reduction in malignant and benign colon tumor sizes, tumors in the lungs and in diverse parts of the alimentary canal principally the esophagus and fore stomach	Salim et al., (2010)

• Picrorhiza kurroa:  It contains chemicals that help stimulate the immune system while killing cancer cells and relieving inflammation (swelling). The clinical trials are carried out to evaluate the antioxidant and anti-neoplastic activities of methanolic and aqueous extracts of roots of Picrorhiza kurroa (Rajkumar et al., 2011).   A spectrophotometric method is used for determining the phenolic content. The use of radical scavenging assays (DPPH· and ·OH), ferric reducing antioxidant properties (FRAP) and thiobarbituric acid (TBA) assay have been integrated for analyzing the antioxidant efficacy of the extracts and testing inhibition of lipid peroxidation. Different cancer cell lines are used to evaluate the cytotoxicity of the extracts tested by XTT assay. The results revealed the efficacy of  Picrorhiza kurroa in showing antioxidant properties. The dosage has been effective in targeting cells towards apoptosis. It is influential in the development of drugs for cancer.
• Piper cubeba: It effectively treats cough, swelling, dysmenorrhea, erectile dysfunction and indigestion. Cubebin is the vital constituent isolated from the seeds of Piper cubeba. Its different types of derivatives are tested for evaluating the in vitro anticancer activity against various types of human cancer cell lines using MTT assay (Rajalekshmi et al., 2016). The result of this test showed anti-cancer effects. The derivatives acted through an apoptosis mediated pathway of cell death, which would effectively develop novel anti-cancer agents. 
• Tribulus terrestris:  It effectively enhances athletic performance and bodybuilding and treats heart and circulatory conditions and sexual issues. Tribulus terrestris represented clinical therapeutic effects against liver cancer cells. The aqueous extract of Tribulus terrestris was orally administered with 800 mg/kg for seven days before gamma irradiation, and the results showed significant radioprotection. When the clinical trial was carried out in mice, the treatment of TT showed protection against radiation damage by inhibiting radiation-induced glutathione depletion and decreasing lipid peroxidation levels in the liver of mice (Kumar et al., 2009). Also, clinical trials were carried out to determine the cytotoxic activity of human fibroblasts using MTT analysis and 3h Thymidine incorporation to assess cell viability and proliferation (Neychev et al., 2007). The results showed that they were less toxic for normal human skin fibroblasts.
• Withania somnifera: It possesses pharmacological properties, such as ant-microbial, anti-inflammatory, anti-stress, anti-tumor, neuroprotective, cardioprotective, and many more for treating biological approaches. Withanolides are isolated from W. somnifera, which shows its efficacy in inhibiting the growth of cancerous cells in the central nervous system, lungs, breasts, and colon cell lines. In vitro cytotoxic evaluation of 50% ethanolic extract of root, stem, and leaves against different human cancer cell lines, e.g., prostate, lungs, colon, and neuroblastoma, showed more effective antitumor activity against prostate and colon cancer than roots and stem extracts (Yadav et al., 2010). Another clinical trial showed anti-carcinogenic activity against urethane-induced lung cancer in adult male albino mice (Achar et al., 2018). The results showed that intake of 200 mg/kg of powdered plant and 125 mg/kg of urethane biweekly for seven months decreased the incidence of tumors. The clinical studies also revealed plants’ antiproliferative activity, which was assessed against human laryngeal carcinoma (Hep2) cells using a microculture tetrazolium assay that resulted in decreased tumor weight in mice (Panjamurthy et al., 2008).

1.11 Astragalus

Astragalus is one of the most common herbs derived from traditional Chinese medicine effective in the treatment of different cancer types such as  breast, colorectal, esophageal, lung and stomach cancers. It is effective in reducing side effects of cancer treatment and improving quality of life. It has anti-inflammatory properties and enhances immune function. It is most often used in combination with other herbs of traditional Chinese medicine.

Different clinical studies have represented an improved survival rate with the treatment using Astragalus. Some of them are described below:

• The use of Astragalus radix shows efficacy in improving the tumor response to chemotherapy (Zhu et al., 2016).
• Astragalus membranaceus has shown efficacy in increasing the chemotherapy completion in breast cancer with the chemotherapy-associated hand-foot syndrome (Yu et al., 2020).
• The use of Astragali radix with other herbal medicines has improved the clinical effectiveness and survival rate in patients with advanced colorectal cancer who are undergoing chemotherapy (Huang et al., 2019).
• The use of astragalus polysaccharide injections in radiotherapy among esophageal cancer patients has shown an improved overall response rate (Zhongguo et al., 2015).
• Astragalus-based botanical therapy is integrated for the patients with small cell lung cancer showing increased effectiveness of platinum-based chemotherapy with improved survival, performance status and tumor response rate (Wang et al., 2016).
• Improved clinical efficacy and overall response are observed with astragalus polysaccharides injection when used with FOLFOX regimen in case of stomach cancer (Zhang et al., 2017).

1.12 European Mistletoe

Mistletoe is the woody plant material belonging to different species. European mistletoe (Viscum album) are the raw mistletoe plants. Its raw plant material and berries are toxic, but it’s sterile extracts have benefits when injected or infused. It consists of various biological active compounds among which lectin is the most important one. It shows toxicity  to cancer cells and is effective in stimulating the immune system, showing anti-cancer activities. Mistletoe preparations are used by administering subcutaneous, intramuscular, or intrapleural injections, or as an intravenous infusion. High-dose of European mistletoe have interrupted the recurrent tumors among the cancer patients with recurrent cancer (von Schoen-Angerer et al., 2015). It supports the immune system by increasing the number and activities of white blood cells, mainly the natural killer (NK) cells.

Different clinical studies have been represented with improved survival rate with the treatment using European Mistletoe. Some of them are described below:

• The use of  European mistletoe is effective in improving survival and prolonged relapse intervals in breast cancer (Ziegler et al., 2010).
• Fewer lung metastases and a lower adjusted hazard ratio for brain metastases, along with significantly longer tumor-related survival, overall survival, disease-free survival and brain metastases-free survival of primary intermediate- to high-risk malignant melanoma patients without distant metastases following surgery are observed (Augustin et al., 2005).
• Effectiveness in improved overall survival rate in ovarian cancer patients have been observed in case of distant metastasis with the use of  mistletoe extracts (Grossarth-Maticek & Ziegler, 2007).
• The patients of pancreatic cancer who have undergone improved adjuvant chemotherapy with gemcitabine after surgery are recommended for using mistletoe showing improved survival rate (Matthes et al., 2010). 

1.13 Turkey Tail Mushroom: 

It is the type of traditional Chinese medicine with formulation of PSK or Krestin™ being majorly used in japan. It is known for enhancing immune-modulating effects and is considered as an adjuvant or supplement in cancer treatment. The major constituents of turkey tail mushrooms is related to its medicinal properties involving β-glucans, PSK (protein bound polysaccharide, β (1-4)D-glucan protein): Krestin (Japanese formulation), PPSP (polysaccharopeptide), and Ergosterol (provitamin D2 derivatives). It shows efficacy in combination with evidence-based conventional treatment, such as chemo/radiotherapy or surgery. PSK (a glycoprotein-bound mixture) is the best-known component of turkey tail showing anticancer mechanism. 

Different clinical studies have been represented with improved survival rate with the treatment using turkey tail mushroom. Some of them are described below:

• Prolonged survival rate in patients with breast cancer have been observed who have used turkey tail mushroom (Eliza et al., 2012).
• It has shown efficacy in improving both the five-year disease-free rate and five-year survival after curative gastrectomy for patients of gastrointestinal cancer (Nakazato et al., 1994).
• Improved overall survival is observed when used as an adjunct with chemo/radiotherapy or surgery in a trial with nasopharyngeal cancer (Zhong et al., 2019).

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