Research Article - Asian Journal of Biomedical and Pharmaceutical Sciences (2017) Volume 7, Issue 60
Tinospora cordifolia an Augmenting Agent for Quality of Life in Cancer: an Overview
Shri Krishna Ayurvedic College, Varanasi, India
- *Corresponding Author:
- Kapil Yadav
Shri Krishna Ayurvedic College, Varanasiv, India
E-mail: [email protected]
Accepted on January 28, 2017
Surgery, chemotherapy and radiotherapy are major approach of cancer treatment and excess reactive oxygen species molecule is generated during chemotherapy. Furthermore, chemotherapy depresses the immunity inviting infection with altered cognitive function. T. cordifolia having free radical scavenging capacity, decreases oxidative stress by increasing glutathione & other anti-oxidant enzyme and down regulate the pro-inflammatory cytokines. It stimulates helper T cellular immune, innate immune response and develops antigen specific immunity also increase the acetylcholine which is responsible for enhancing the cognitive function. Additionally, it inhibits cell proliferation, differentiation and induced apoptosis that prevent anti-tumor activity. Thus, we can assume that impaired quality of life due to chemotherapy in cancer will be well-adjusted by T. cordifolia and also have anti-tumor activity.
T. cordifolia, Immunity, Oxidative stress, Inflammation
Cancer treatment often contains one or more of three possible treatments like surgery, chemotherapy and radiation therapy. Among them chemotherapy is a group of medications act to stop or at least slow down the growth of tumor cells. It is used to kill cancer cell present in body, during chemotherapy normal tissue come in contact of chemotherapeutic agent and resulting in the unwanted side effects. Radiation therapy uses a beam of high energy radiation that targets the tumour while leaving the surrounding tissue less affected. Radiation acts to destroy DNA which can kill the cancer cells. Due to damaging the normal tissues either by chemotherapy or radiotherapy, it leads to numerous side effects like nausea, vomiting, fatigue, anorexia, constipation, hair loss, diarrhoea, sleep disturbance, headache along with these long term toxicity like laryngitis, pharyngitis, esophagitis, stomatitis, dry skin, hepatotoxicity, infertility and cognitive function may also deteriorate the quality of life [1,2]. Quality of life (QoL) perceives life satisfaction i.e. physical health, family, education, employment, wealth, religious beliefs, finance and the environment and has wide range of perspectives, including the fields of international development, healthcare, politics and employment [3,4].
It has been scientifically validated that adjunct treatment with herbo-mineral and metallic ayurvedic drugs appear to have a significant effect on reducing the toxic side effects of chemotherapy drugs in cancer patients . In ayurvedic classics, chandan (Santalum album), sariva (Hemidesmus indicus), manjistha (Rubia cordifolia), bhumi amalki (Phyllanthus niruri), kalmegh (Andrographis paniculata), guduchi (Tinospora cordifolia), amalaki (Emblica officinalis) etc. has been reported for skin care, hepato-protective as well as cognitive enhancer  and protecting unwanted effect of chemotherapy and radiotherapy. Additionally, various herbs are documented for anti-vomiting, anti-pyretic, digestive stimulant etc. that will also helpful in enhancing quality of life. In present review we are trying to explore the pharmacological properties of T. cordifolia as quality of life enhancer with scientific facts and figure.
Ayurvedic materia media
Herbs, metals & minerals and animal products are three pillar of ayurvedic material medica. Among them herbs occupy the major seat for treatment of diseases as well as maintenance of health. Herbs have various chemical agents which belong to different classes, such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics, aliphatic compounds and polysaccharides. Due to presence of these chemical constitute herbs is responsible for numerous properties as per ancient texts of ayurveda, like rasayana, sangrahi, balya, agnideepana, dahnashaka, mehnashaka, kasaswasahara and jwarhara etc. and antipyretic, antispasmodic, anti-inflammatory, antioxidant, anti-allergic, anti-stress, hepato-protective, immuno-modulatory, anti-neoplastic activities etc.
In contemporary sciences [7-9] it has been quoted that T. cordifola has sangrahik, vatahar, deepaniya, shleshma-shonitvibandh pacifying properties which may responsible for disease curing as well as improving health .
T. Cordifolia as quality of life (qol) enhancer
In ayurvedic science T. cordifolia is used in ayurveda to enhance vitality by improves the ability of macrophages, immune system cell. Along with this it is reported as antiallergic, adaptogen-like properties which protect against DNA damage induced by the environment and radiation therapy. In this way T. cordifolia may improve the quality of life even in cancer patients, the possible way of its action is summarized as mentioned.
Anti-inflammatory activity of T. cordifolia
It has been reported that chronic inflammation is moderately associated with lower quality of life (QoL) levels . Most of the cancers are outcome of chronic irritation, inflammation and infection and it assists tumor growth, spread around the body, thus it seems that inflammatory cells are an indispensable sponsor in the neoplastic process, promotion, proliferation, survival and migration. It has been suggested that antiinflammatory approaches play a big role in cancer prevention and treatment in the future [12,13]. Enormous medicinal plants have been listed in material medica of ayurveda which have potent anti-inflammatory activity such as patala (Stereospermum suaveolens), gambhari (Gmelina arborea), agnimanth (Premna integrifolia), gokshur (Tribulus terrestirs), erand (Ricinus communis) and guduchi (T. cordifolia) etc. Among them guduchi occupied significant seat for management of different disorders, it has been reported that compound (1,4)-a-D-glucan (a-D-glucan), derived from T. cordifolia activate human lymphocytes with downstream synthesis of the pro-inflammatory cytokines such as tumor necrosis factor (TNF- α), interleukin beta (IL-1b), interleukin (IL-6,) IL-18, interferon’s (IFN-c).  Among them TNF- α bind with tumor necrosis factor receptor superfamily member 1A /tumor necrosis factor receptor 1 (TNFRSF1A/TNFR1) and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B/TNFBR) receptors, which regulate the biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism and may concern with variety of diseases like cancer, autoimmune diseases etc . Furthermore, TNF- α and IFN- γ, co-expression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 . It has been also reported that anti-inflammatory activity of T. cordifoliaresembles that of non-steroidal anti-inflammatory agents  and possess significant antipyretic activity (when given orally) [18,19]. Thus we can assume that T. cordifoliadiminished pain, fever etc. (common side effect of chemo-radiotherapy) when associated with chemotherapy agent by anti-inflammatory and anti-pyretic activity of T. cordifoliaand prevent the genesis and growth of cancer.
Immunomodulatory activity of T. cordifolia
Cancers inhibit the normal immune response and enabling malignant cells to grow and spread through variety of mechanisms [20,21]. It has been reported that immune system is capable of eliminating tumor cells thus compromised immune system may have an increased incidence of cancer and are more likely to develop malignant tumors [22,23]. It has reported that immunomodulator improves the health-related quality of life [24,25]. So that immunotherapies are expected to become a treatment option for quality of life may be characterized within physical, material, social, emotional wellbeing, development and enhance activity cancer therapy along with the traditional methods such as surgery, radiation and chemotherapy. Used in combination with these three traditional methods, immunotherapies may upsurge the probability of long-term remissions in cancer.
It has been reported that IL 10 decreases immune pathology due to uncontrolled inflammation and inhibits sterile immunity  and IL 12 stimulate and maintenance of T helper (Th1) cellular immune responses, including the normal host defense against various intracellular pathogens and Th 1 further activate macrophages which are responsible for cell mediated immunity and phagocyte dependent protective responses. IL 18 increases NK cell activity which is part of innate immune response and develops antigen specific immunity and induces production of IFNγ  that directly inhibit viral replication, and shows immune-stimulatory and immune-modulatory effects . Additionally, it executes diverse biological functions like host & anti-bacterial defense, cell cycle, apoptosis  and also associated with cytostatic/cytotoxic and anti-tumor functions by activated human T lymphocytes. Alpha-glucan polysaccharide present in T. cordifolia activates natural killer (NK) cells, T cells, and B cells and also induces production of interleukin (IL)-1, IL-6, IL-12, IL-18, interferon-gamma .
Due to stimulation of IL-12, IL-18, T. cordifolia stimulates Th1 cellular immune responses and innate immune response and also develops antigen specific immunity. Additionally T. cordifolia have a immunomodulation property through activation of macrophage  and increase in the WBC counts and bone marrow cells which stimulate haemopoetic [32,33]. Thus it shows immune stimulatory and immuno-modulatory activity. It has been reported that IL-10 was regarded as an immune suppressive cytokine that hindered anti-tumor immunity . It has been reported that G1-4A obtained from T. cordifolia down regulate the IL-10. It has been reported that G1-4A which is a Polysaccharide obtained from T. cordifolia down regulate the IL-10 .
Thus we can assume that T. cordifolia decreases the immune suppression caused by IL 10 i.e. T. cordifolia may have immuno-stimulatory properties. Cancer therapy is associated with increased risk of development of tuberculosis [35,36] and it has been reported that combination of G1-4A (compound present in T. cordifolia) with Isoniazid (INH) exhibited better protection against MTB compared to that due to INH or G1-4A alone, suggesting its potential as adjunct therapy. Thus, G1-4A might improve the therapeutic efficacy of existing anti-tubercular drugs and provide an attractive strategy for the development of alternative therapies to control tuberculosis  in immune-compromised patients.
Anti-oxidant activity of T. cordifolia
Anti-cancerous agent kills the cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. And increasing concentration of exogenous oxidants modifies vital proteins, leading to cardiac muscle dysfunction and causes muscle weakness . Reactive oxygen species (ROS) damages macromolecules, especially DNA, which undergoes strand breakage, change and release of bases as well as modification of sugar moieties [38,39]. Thus promoting a series of pathological event viz. cancer and aging. Furthermore, chemotherapy drugs cause oxidative stress in noncancerous tissues which is negatively correlated with QoL. Moreover, oxidative stress leads to destabilization and disintegration of the cell membrane [40,41]. Additionally high ROS levels causes oxidation of protein which in turn induce oxidative stress and also decrease in the tissue glycoprotein, a potential mediator of pathogenic conditions . It has been reported that antioxidants provide relief in cancer patients from debilitating muscle weakness, leading to improved quality of life. ROS are scavenged by cellular enzymatic and nonenzymatic antioxidants, which protect from oxidative stress. Glutathione (GSH) is an important non enzymatic antioxidant scavenging of free radicals and used to assess oxidative stress and chemo-preventive ability . In previous research, antioxidant supplementation with chemotherapy and radiotherapy apparently decreased oxidative stress, maintained hemoglobin levels, and improved QoL . T. cordifolia increases level of GSH as well as glutathione peroxidase (GPx) glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) that protects harmful effects of lipid peroxidation and act as chemo-protective agent . It has been reported that T. cordifolia increased the tissue glycoprotein and reduces oxidative stress  which protect from destabilization and disintegration of the membrane and improve quality of life.
Chemotherapy agents commonly produce cognitive impairment and can persist for 1 and 2 years after the completion of chemotherapy [47,48] and lasting between 4 and 10 years after chemotherapy [49,50] anticancer treatment regarding attention deficits, memory loss and thought processes and receiving increasing attention after long term and during & shortly after chemotherapy and for cancer. It is found that cognitive difficulties persist in 70% of cancer patients [51-53] and also reported that standardized neuropsychological treatment shows mild to moderate effects on cognitive performance in 15-50% patients [54,55]. The anticancerous drug (cyclosporine) produced impairment of learning and memory may be associated with degeneration of hippocampal neurons. T. cordifolia enhances cognition (learning and memory) by immune stimulation and increasing the synthesis of acetylcholine that is important neurotransmitter . In ayurvedic literature, T. cordifolia is quoted as best medhya rasayana (learning and memory enhancer)  and useful for treatment of Bhrama (Vertigo), anti-stress activity  with moderate degree of behaviour disorders and mental deficit, along with improvement in IQ levels . It has been reported that cognitive stimulation therapy (CST) will be effective to improve their cognitive functioning as well as QoL . T. cordifolia has also been shown to enhance cognition (learning and memory) and reverse cyclosporine induced memory deficit. Along with its radio and chemo-protective effects, T. cordifolia has also been reported for neuro-protective potential by modulating antioxidant enzyme system of brain tissue, thus T. cordifolia may improve QoL.
Anti-tumor activity of T. cordifolia
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body . It is the disease of tissue growth regulation and normal cell to transform into a cancer cell, the genes that regulate cell growth and differentiation must be altered. Characteristic abilities developed by cancers are divided into categories, specifically evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism and evasion of immune destruction [62,63]. The term apoptosis is often used interchangeably with programmed cell death. In the strictest sense, programmed cell death may be applied to other forms of cell death that require gene expression without fulfilling some, or all, of the morphological criteria of apoptosis . Naturally occurring phytochemicals display an active cancer preventive strategy to inhibit, delay, or reverse human carcinogenesis. It has been reported that 13-n-octyl-palmatine (4d) displayed potent cytotoxic activity against seven cancer cells and also improve the anti-proliferative activity, improve the antiproliferative activity and exhibit significant antitumor activity against HL-60 leukemic cells . It has been reported that T. cordifolia inhibit cell proliferation, differentiation and tumorassociated macrophages (TAM)  and induced cell death and also act as chemo-preventive agents through the induction of apoptosis . Also, T. cordifolia extracts has antineoplastic as comparable as or better than doxorubicin treatment . It is found that palmatine, yellow color compound is active constituents of a number of plants, such as T. cordifolia [69,70]. Thus T. cordifolia helpful in treatment of cancer by the presence of palmatine as active compound. The polysaccharide fraction from T. cordifolia is effective in reducing the metastatic potential of B16-F10 melanoma cells.
Hazardous effect of chemotherapy such as immunosuppression, impairment of cognition, generation of reactive oxygen species which hamper the quality of life will be well adjusted by T. cordifolia by its pharmacological properties like immuno-stimulant, cognitive enhancer and decreasing oxidative stress. Likewise, it also acts has antitumor activity. Thus T. cordifolia improve the quality of life in cancer patient and it may be beneficial if used with chemotherapeutic agent.
- Lu QR, Wang YL, Zhao XH. Study on the quality of life of cervical cancer patients. Chin Nurs Res. 2010; 24: 946–48.
- Vistad I, Fosså SD, Dahl AA. A critical review of patient-rated quality of life studies of long-term survivors of cervical cancer. Gynecol Oncol. 2006; 102: 563-572.
- Quality of life available on https://en.wikipedia.org/wiki/Quality_of_life last assessed on 18.9.2016
- Charles ST, Carstensen LL. Social and emotional aging. Annu Rev Psychol. 2010; 61: 383-409.
- Deshmukh V, Kulkarni A, Bhargava S, Patil T, Ramdasi V, Gangal S, Godse V, Datar S, Gujar S, Sardeshmukh S. Effectiveness of combinations of Ayurvedic drugs in alleviating drug toxicity and improving quality of life of cancer patients treated with chemotherapy. Support Care Cancer. 2014; 22: 3007.
- Samhita CC. Varanasi: Chaukhambha Bharti Academy. 2005.
- The Ayurvedic Pharmacopoeia of India. Part I. 1st ed. Vol. 1. New Delhi: Department of AYUSH, Ministry of Health and Family Welfare. 2001; p. 53–5.
- Indian medicinal plants. 1st ed. Vol. V. Kottakkal: Arya Vaidya sala. 1994; p. 283.
- Chunekar KC, Pandey GS. Guduchyadi Varga. Bhavprakash Nidhantu. Varanasi: Chaukhambha Bharati Academy. 2006. p. 269.
- Samhita CC. Varanasi: Chaukhambha Bharti Academy. 2005.
- Faugere M, Micoulaud-Franchi JA, Alessandrini M, Richieri R, Faget-Agius C, Auquier P, Lançon C, Boyer L. Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study. Sci Rep 2015; 5: 10793.
- Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420: 860-867.
- Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006; 79: 123-130.
- TNF tumor necrosis factor, Homo sapiens (human) available on http://www.ncbi.nlm.nih.gov/gene/7124 last assessed on 20.09.2016
- Rodriguez-Galan MC, Reynolds D, Correa SG, Iribarren P, Watanabe M, Young HA. Coexpression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its antitumor capacity. J Immunol. 2009; 183:740-48.
- Gulati OD, Pandey DC. Anti-inflammatory activity of Tinospora cordifolia, Rheumatism. 1982; 17:76-83.
- Leghari MY, Muzaffar NA, Haq IU. Pharmacological testing of antipyretic activity of Tinospora cordifolia. J Pharmacy University. 1984; 3: 31-41.
- Vedavathy S, Rao KN. Short communication: Antipyretic activity of six indigenous medicinal plants of Tirumala Hills, Andhra Pradesh, India. J Ethnopharmacology 1991; 33: 193-6.
- Murphy K, Travers P, Walport M. Janeway's Immunobiology. 7th ed. Garland Science, Taylor & Frances Group, LLC. New York, NY: 2008.
- Ribas A, Butterfield LH, Glaspy JA, Economou JS. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol. 2003; 21: 2415-2432.
- Le Mire L, Hollowood K, Gray D, Bordea C, Wojnarowska F. Melanomas in renal transplant recipients. Br J Dermatol. 2006; 154: 472-477.
- Immune System and Cancer available on http://www.fightcancerwithimmunotherapy.com/immunesystemandcancer/default.
- Alvarez-Mon M, Miravitlles M, Morera J, Callol L, Alvarez-Sala JL. Treatment with the immunomodulator AM3 improves the health-related quality of life of patients with COPD. Chest. 2005; 127: 1212-1218.
- Kim KC, Yook JH, Eisenbraun J, Kim BS, Huber R. Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma – a randomized, controlled pilot study BMC Complementary and Alternative Medicine 2012;12:172.
- Interleukin Definition available on http://www.sinobiological.com/What-are-Interleukins-a-6072.html.
- Interleukin https://en.wikipedia.org/wiki/Interleukin.
- Interferon gamma https://en.wikipedia.org/wiki/Interferon gamma.
- Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004; 75: 163-189.
- Gupta PK, Chakraborty P, Kumar S, Singh PK, Rajan MG, Sainis KB, Kulkarni S. G1-4A, A Polysaccharide from Tinospora cordifolia Inhibits the Survival of Mycobacterium tuberculosis by Modulating Host Immune Responses in TLR4 Dependent Manner. PLoS One. 2016; 11: e0154725.
- More P, Pai K. Immunomodulatory effects of Tinospora cordifolia (Guduchi) on macrophage activation. Biol Med. 2011; 3: 134-40.
- Aher VD, Wahi AK. Pharmacological Study of Tinospora cordifolia as An Immunomodulator. J Curr Pharm Res. 2010; 2: 5254.
- Umretia B, Vaishnav P, Patgiri B, Shukla V. Immunomodulatory activity of Guduchi Ghana (Aqueous Extract of Tinospora cordifolia Miers). NJIRM. 2013; 4: 90-96.
- Dennis KL, Blatner NR, Gounari F, Khazaie K. Current status of interleukin-10 and regulatory T-cells in cancer. Curr Opin Oncol. 2013; 25: 637-645.
- Feld R, Bodey GP, Gröschel D. Mycobacteriosis in patients with malignant disease. Arch Intern Med. 1976; 136: 67-70.
- Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease. A review of 201 cases. Cancer 1974; 33: 850-858.
- Andrade FH, Reid MB, Allen DG, Westerblad H. Effect of hydrogen peroxide and dithiothreitol on contractile function of single skeletal muscle fibres from the mouse. J Physiol Online. 1998;509:565–75.
- Henle ES, Linn S. Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide. J Biol Chem 1997; 272: 19095-19098.
- Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000; 21: 361-370.
- Stohs SJ, Bagchi D, Hassoun E, Bagchi M. Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol. 2000; 19: 201-213.
- Renugadevi J, Prabu SM. Quercetin protects against oxidative stress-related renal dysfunction by Cd in rats. Exp Toxicol Pathol. 2010; 62471–81.
- Ganesan B, Buddhan S, Anandan R, Sivakumar R, AnbinEzhilan R. Antioxidant defense of betaine against isoprenaline-induced myocardial infarction in rats. Mol Biol Rep. 2010; 37: 1319-1327.
- Hamsa TP, Kuttan G. Tinospora cordifolia ameliorates urotoxic effect of cyclophosphamide by modulating GSH and cytokine levels. Exp Toxicol Pathol. 2012; 64: 307-314.
- Fuchs-Tarlovsky V, Rivera MA, Altamirano KA, Lopez-Alvarenga JC, Ceballos-Reyes GM. Antioxidant supplementation has a positive effect on oxidative stress and hematological toxicity during oncology treatment in cervical cancer patients. Support Care Cancer. 2013; 21: 1359-63.
- Ray G, Husain SA. Oxidants, antioxidants and carcinogenesis. Indian J Exp Biol 2002; 40: 1213-1232.
- Padmaa VV, Baskaranb R, Divyaa R, Priyaa LB, Saranyaa S. Modulatory effect of Tinospora cordifolia extract on Cd-induced oxidative stress in Wistar rats. Integr Med Res. 2016; 5: 48-55.
- Ahles TA, Saykin AJ, McDonald BC, Li Y, Furstenberg CT, Hanscom BS, Mulrooney TJ, Schwartz GN, Kaufman PA. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol. 2010; 28: 4434–40.
- Schagen SB, Muller MJ, Boogerd W, Mellenbergh GJ, VanDam FS. Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst. 2006; 98: 1742-45.
- de Ruiter MB, Reneman L, Boogerd W, Veltman DJ, van Dam FS, Nederveen AJ Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Hum Brain Mapp. 2011; 32: 1206-19.
- Kreukels BP, Schagen SB, Ridderinkhof KR, Boogerd W, Hamburger HL, Muller MJ, van Dam FS. Effects of high-dose and conventional-dose adjuvant chemotherapy on long-term cognitive sequelae in patients with breast cancer: an electrophysiologic study. Clin Breast Cancer. 2006; 7: 67-78.
- Vardy J, Wefel J S, Ahles T, Tannock IF, Schagen SB. Cancer and cancertherapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Ann Oncol. 2008; 1: 623–29.
- Castellon SA, Ganz PA, Bower JE, Petersen L, Abraham L. Greendale GA. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol. 2004; 26: 955–69.
- van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standarddose chemotherapy. J. Natl. Cancer Inst. 1998; 90:210-18.
- Joly F, Rigal O, Noal S, Giffard B. Cognitive dysfunction and cancer: which consequences in terms of disease management? Psychooncology. 2011; 20: 1251-58.
- Vardy J, Tannock I. Cognitive function after chemotherapy in adults with solid tumours. Crit Rev Oncol Hematol 2007; 63: 183-202.
- Hagan JJ, Morris RGM. The Cholinergic hypothesis of memory. A review of animals experiment. Handbook of Psychopharmacology In: Iverson LL, Iverson S, snyder SH eds. Newyork: Plenum; 1988; 20: 237-323.
- Bairy KL, Rao Y, Kumar KB. Efficacy of Tinospora cordifolia on learning and memory in healthy volunteers: A double blind, randomized, placebo controlled study. Iranian J Pharmacol Therap. 2004; 3: 57–60.
- Singh J, Sinha K, Sharma A, Mishra NP, Khanuja SP. Traditional uses of Tinospora cordifolia (Guduchi). J Med Aromat Plant Sci. 2003; 25: 748–51.
- Singh SS, Pandey SC, Srivastava S, Gupta VS, Patro B, Ghosh AC. Chemistry and medicinal properties of Tinospora Cordifolia (Guduchi). Indian J Pharmacol. 2003; 35: 83-91.
- Toh HM, Ghazali SE, Subramaniam P. The Acceptability and Usefulness of Cognitive Stimulation Therapy for Older Adults with Dementia: A Narrative Review. Int J Alzheimer’s Dis. 2016.
- World Health Organization. February 2014. Retrieved 10 June 2014, National Cancer Institute. Retrieved 10 June 2014.
- Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100: 57–70.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-674.
- Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA. 2000; 97: 14376-14381.
- Kuo CL, Chou CC, Yung BY. Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells. Cancer Lett. 1995; 93: 193-200.
- Singh SM, Singh N, Shrivastava P. Effect of alcoholic extract of Ayurvedic herb Tinospora cordifolia on the proliferation and myeloid differentiation of bone marrow precursor cells in a tumor-bearing host. Fitoterapia. 2006; 77: 1-11.
- Thippeswamy G, Salimath BP. Induction of caspase-3 activated DNase mediated apoptosis by hexane fraction of Tinospora cordifolia in EAT cells. Environ Toxicol Pharmacol. 2007; 23: 212–20.
- Jagetia GC, Nayak V, Vidyasagar MS. Evaluation of the antineoplastic activity of guduchi (Tinospora cordifolia) in cultured HeLa cells. Cancer Lett. 1998; 127:71-82.
- Giri P, Hossain M, Kumar GS. RNA Specific Molecules: Cytotoxic Plant Alkaloid Palmatine Binds Strongly to Poly(A). Bioorganic & Medicinal Chemistry Letters. 2006; 16: 2364–68.
- Zhang L, Li J, Ma F, Yao S, Li N, Wang J, Wang Y, Wang X, Yao Q. Synthesis and cytotoxicity evaluation of 13-n-alkyl berberine and palmatine analogues as anticancer agents. Molecules. 2012; 17: 11294-11302.
- Leyon PV, Kuttan G. Inhibitory effect of a polysaccharide from Tinospora cordifolia on experimental metastasis. J Ethnopharmacol. 2004; 90: 233-237.