Withania Somnifera: A New Approach To Cancer
Keywords:
Ashwagandha, Withania Somnifera, Oral cancer, Ayurvedic herb
Abstract
Cancer is a hyper proliferative disorder characterized by the abnormal proliferation of cells that invades into the adjacent tissues and causes the destruction. Many cancers are hereditary, other arise from the internal and external environmental factor. Various treatment modalities available for cancer are Surgery, Radiation, Chemotherapy and targeted therapy. Inspite of major advances in drug discovery, research is still undergoing to understand complex biology of cancer with new therapeutics available. A popular ayurvedic herb Withania Somnifera (WS) also known as Indian Winter Cherry and Indian Ginseng is used as a traditional medicine for various cancers. The results of the studies carried out on WS and its chemical components like Withaferin A(WA), Withanolide D (WithaD) etc, describe that it is effective in prevention and treatment of different kinds of cancer like colon, blood, lung, skin, breast, renal, fibrosarcoma, prostate, pancreatic, renal, malignant melanoma, osteosarcoma by preventing proliferation and progression of cancer cells, alteration in hematological and biochemical parameters, modulation of cell cycle markers etc. Withania somnifera can be given alone or in combination with synthetic drugs. Identification of novel natural anticancer compound is highly demanding for prevention and treatment of cancer. However, multicentric long term clinical studies should be carried out to provide complementary and alternative therapy.DOI: 10.21276/AABS.1838References
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2. Wadhwa R, Singh R, Gao R, Shah N, Widodo N, Nakamoto T et al. Water Extract of Ashwagandha Leaves Has Anticancer Activity: Identification of an Active Component and Its Mechanism of Action. PLoS ONE 2013;8(10):e77189.
3. Metri K, Bhargav H, Chowdhury P, Koka PS. Ayurveda for chemo-radiotherapy induced side effects in cancer patients. J Stem Cell 2013;8(2):115-29.
4. Palliyaguru DL, Singh SV, Kensler TW. Withania Somnifera:From prevention to treatment of cancer. Mol Nutr Food Res 2016;60(6):1342-53.
5. Balachandran P, Govindarajan R. Cancer-an Ayurvedic perspective. Pharmacol Res 2005;51(1):19-30.
6. Josh RA. Ashwagandha (Withania somnifera) as anticancer herb: An overview. International Journal Of Pharmaceutical Research And Bio-Science 2017;6(1): 74-92.
7. Khazal KF, Hill DL, Grubbs CJ. Effect of withania somnifera root extract on spontaneous estrogen receptor-negative mammary cancer in mmtv/neu mice. Anticancer Res 2014; 34(11): 6327–32.
8. Choi BY, Kim BW. Withaferin-A Inhibits Colon Cancer Cell Growth by blocking STAT3 Transcriptional Activity. J Cancer Prev 2015;20(3):185-92.
9. Mishra LC, Singh BB, Dagenais S. Scientific Basis for the Therapeutic Use of Withania somnifera (Ashwagandha): A Review. Altern Med Rev 2000;5(4):334-46.
10. Singh G, Sharma PK, Dudhe R and Singh S. Biological activities of Withania somnifera. Annals Biol Res 2010;1(3):56-63.
11. Muralikrishnan G, Dinda AK, Shakeel F. Immunomodulatory effects of Withania somnifera on azoxymethane induced experimental colon cancer in mice. Immunol Invest 2010;39(7):688-98.
12. Muralikrishnan G, Amanullah S, Basha MI, Dinda AK, Shakeel F. Modulating effect of Withania somnifera on TCA cycle enzymes and electron transport chain in azoxymethane-inducedcolon cancer in mice. Immunopharmacol Immunotoxicol 2010;32(3):523-527.
13. Yadav B, Bajaj A, Saxena M, Saxena AK. In Vitro Anticancer Activity of the Root, Stem and Leaves of Withania Somnifera against Various Human Cancer Cell Lines. Indian J Pharm Sci 2010;72(5):659- 63.
14. Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther 2010;9(1):202-10.
15. Das T, Roy KS, Chakrabarti T, Mukhopadhyay S, Roychoudhury S. Withaferin A modulates the Spindle Assembly Checkpoint by degradation of Mad2-Cdc20 complex in colorectal cancer cell lines. Biochem Pharmacol 2014;91(1):31-9.
16.Malik F, Kumar A, Bhushan S, Khan S, Bhatia A, Suri KA et al. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine. Apoptosis 2007;12(11):2115-33.
17.Mondal S, Mandal C, Sangwan R, Chandra S, Mandal C. Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Mol Cancer 2010;9:239.
18.Senthil V, Ramadevi S, Venkatakrishnan V, Giridharan P,Lakshmi BS, Vishwakarma RA et al. Withanolide induces apoptosis in HL-60 leukemia cells via mitochondria mediated cytochrome c release and caspase activation. Chem Biol Interact 2007;167(1):19-30.
19.Turrini E, Calcabrini C, Sestili P, Catanzaro E, Gianni ED, Diaz AR,et al. Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells. Toxins 2016;8(5):147.
20. Senthilnathan P, Padmavathi R, Banu SM, Sakthisekaran D. Enhancement of antitumor effect of paclitaxel in combination with immunomodulatory Withania somnifera on benzo(a) pyrene induced experimental lung cancer. Chem Biol Interact 2016;159(3):180-5.
21. Choudhary MI, Hussain S, Yousuf S, Dar A, Mudassar, Atta-ur- Rahman. Chlorinated and diepoxy withanolides from Withania somnifera and their cytotoxic effects against human lung cancer cell line. Phytochemistry 2010;71(17-18):2205-9.
22. Liu X, Chen L, Liang T, Tian XD, Liu Y, Zhang T. Withaferin A induces mitochondrial-dependent apoptosis in non-small cell lung cancer cells via generation of reactive oxygen species. J BUON 2017;22(1):244-50.
23. Singh N, Singh SP, Nath R, Singh DR, Gupta ML, Kohli RP, Bhargava KP. Prevention of urethane induced Lung adenomas by Withania somnifera (L) Dunal in albino mice. Int J of Crude Res 1986; 24(2):90-100.
24. Padmavathi B, Rath PC, Rao AR, Singh RP. Roots of withania somnifera inhibit forestomach and skin carcinogenesis in mice. Evid Based Complement Alternat Med 2005;2(1):99-105.
25. Mathur S, Kaur P, Sharma M, Katyal A, Singh B, Tiwari M, et al. The treatment of skin carcinoma, induced by UV B radiation, using 1-oxo-5beta, 6beta-epoxy-witha-2-enolide, isolated from the roots of Withania somnifera, in a rat model. Phytomedicine 2004;11(5):452-60.
26. Prakash J, Gupta SK, Dinda AK. Withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in Swiss albino mice. Nutr Cancer 2002;42(1):91-7.
27. Li W, Zhang C, Du H, Huang V, Sun B, Harris JP, et al. Withaferin A Suppresses the Up-Regulation of Acetyl-CoA Carboxylase 1 and Skin Tumor Formation in a Skin Carcinogenesis Mouse Model. Mol Carcinog 2016;55(11):1739-46.
28. Li W, Zhao Y. Withaferin A suppresses tumor promoter 12-O-tetradecanoylphorbol 13-acetate-induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells. Cancer Sci 2013;104(2):143-8.
29. Yang ES, Choi MJ, Kim JH, Choi KS, Kwon TK. Withaferin A enhances radiation-induced apoptosis in Caki cells through induction of reactive oxygen species, Bcl-2 downregulation and Akt inhibition. Chem Biol Interact 2011;190(1):9-15.
30. Um HJ, Min KJ, Kim DE, Kwon TK. Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun 2012;427(1):24-9.
31. Choi MJ, Park EJ, Min KJ, Park JW, Kwon TK. Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells. Toxicol In Vitro 2011;25(3):692-98.
32. Xu YM, Brooks AD, Wijeratne EM, Henrich CJ, Tewary P, Sayers TJ, et al. 17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor‑α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis: Structure−Activity Relationships. J Med Chem 2017;60(7):3039-51.
33. Roy RV, Suman S, Das TP, Luevano JE, Damodaran C. Withaferin-A induces mitotic catastrophe and growth arrest in prostate cancer cells. J Nat Prod 2013;76(10):1909-15.
34. Aalinkeel R, Hu Z, Nair BB, Sykes DE, Reynolds JL, Mahajan SD, et al. Genomic Analysis Highlights the Role of the JAK-STAT Signaling in the Anti-proliferative Effects of Dietary Flavonoid—‘Ashwagandha’ in Prostate Cancer Cells. Evid Based Complement Alternat Med 2010;7(2):177-87.
35. Nishikawa Y, Okuzaki D, Fukushima K, Mukai S, Ohno S, Ozaki Y, et al. WithaferinA Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells. PLoS ONE 2015;10(7):e0134137.
36. Srinivasan S, Ranga RS, Burikhanov R, Han SS, Chendil D. Par-4–Dependent Apoptosis by the Dietary Compound Withaferin A in Prostate Cancer Cells. Cancer Res 2007;67(1):246-53.
37. Li X, Zhu F, Jiang J, Sun C, Zhong Q, Shen M, et al. Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells. Autophagy 2016;12(9):1521-37.
38. Li X, Zhu F, Jiang J, Sun C, Wang X, Shen M, et al. Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells. Cancer Lett 2015;357(1):219-30.
39. Yu Y, Hamza A, Zhang T, Gu M, Zou P, Newman B, et al. Withaferin A Targets Heat Shock Protein 90 in Pancreatic Cancer Cells. Biochem Pharmacol 2010;79(4):542-51.
40. Sarkar S, Mandal C, Sangwan R, Mandal C. Coupling G2/M arrest to the Wnt/ β-catenin pathway restrains pancreatic adenocarcinoma. Endocr Relat Cancer 2014;21(1):113-25.
41. Davis L, Kuttan G. Effect of Withania somnifera on 20-methylcholanthrene induced fibrosarcoma. J Exp Clin Cancer Res 2000;19(2):165-7.
42. Prakash J, Gupta SK, Kochupillai V, Singh N, Gupta YK, Joshi S. Chemopreventive activity of Withania somnifera in experimentally induced fibrosarcoma tumours in Swiss albino mice. Phytother Res 2001;15(3):240-44.
43. Kaileh M, Vanden Berghe W, Boone E, Essawi T, Haegeman G. Screening of indigenous Palestinian medicinal plants for potential anti-inflammatory and cytotoxic activity. J Ethnopharmacol 2007; 113(3):510-16.
44. Mayola E, Gallerne C, Esposti DD, Martel C, Pervaiz S, Larue L, et al. Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2. Apoptosis 2011;16(10):1014-27.
45. Kalthur G, Mutalik S, Pathirissery UD. Effect of Withaferin A on the Development and Decay of Thermotolerance in B16F1 Melanoma: A Preliminary Study. Integr Cancer Ther 2009;8(1):93-7.
46. Halder B, Singh S, Thakur SS. Withania somnifera Root Extract Has Potent Cytotoxic Effect against Human Malignant Melanoma Cells. PLoS ONE 2015;10(9):e0137498.
47. Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis 2011;32(11):1697-705.
48. Jha AK, Nikbakht M, Capalash N, Kaur J. Demethylation of RARβ2 Gene Promoter by Withania somnifera in HeLa Cell Line. European J Med Plants 2014;4(5):503-10.
49. Lee DH, Lim IH, Sung EG, Kim JY, Song IH, Park YK, et al. Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway. Oncol Rep 2013;30(2):933-8.
50. Li AX, Sun M, Li X. Withaferin-A induces apoptosis in osteosarcoma U2OS cell line via generation of ROS and disruption of mitochondrial membrane pote
ntial. Eur Rev Med Pharmacol Sci 2017;21(6):1368-74.
51. Lv TZ, Wang GS. Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins. Exp Ther Med 2015;10(1):323-29.
52. Yang Z, Garcia A, Xu S, Powell DR, Vertino PM, Singh S, et al. Withania somnifera Root Extract Inhibits Mammary Cancer Metastasis and Epithelial to Mesenchymal Transition. PLoS ONE 2013;8(9):e75069.
53. Lee J, Hahm ER, Marcus AI, Singh SV. Withaferin A inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol Carcinog 2015;54(6):417-29.
54. Hahm ER, Lee J, Singh SV. Role of mitogen-activated protein kinases and Mcl-1 in apoptosis induction by withaferin A in human breast cancer cells. Mol Carcinog 2014;53(11):907-16.
55. Lee J, Sehrawat A, Singh SV. Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast Cancer Res Treat 2012;136(1):45-56.
56. Hahm ER, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is associated with suppression of inhibitor of apoptosis family protein expression. Cancer Lett 2013;334(1):101-8.
57. Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A Causes FOXO3a- and Bim-Dependent Apoptosis and Inhibits Growth of Human Breast Cancer Cells In vivo. Cancer Res 2008;68(18):7661-9.
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2. Wadhwa R, Singh R, Gao R, Shah N, Widodo N, Nakamoto T et al. Water Extract of Ashwagandha Leaves Has Anticancer Activity: Identification of an Active Component and Its Mechanism of Action. PLoS ONE 2013;8(10):e77189.
3. Metri K, Bhargav H, Chowdhury P, Koka PS. Ayurveda for chemo-radiotherapy induced side effects in cancer patients. J Stem Cell 2013;8(2):115-29.
4. Palliyaguru DL, Singh SV, Kensler TW. Withania Somnifera:From prevention to treatment of cancer. Mol Nutr Food Res 2016;60(6):1342-53.
5. Balachandran P, Govindarajan R. Cancer-an Ayurvedic perspective. Pharmacol Res 2005;51(1):19-30.
6. Josh RA. Ashwagandha (Withania somnifera) as anticancer herb: An overview. International Journal Of Pharmaceutical Research And Bio-Science 2017;6(1): 74-92.
7. Khazal KF, Hill DL, Grubbs CJ. Effect of withania somnifera root extract on spontaneous estrogen receptor-negative mammary cancer in mmtv/neu mice. Anticancer Res 2014; 34(11): 6327–32.
8. Choi BY, Kim BW. Withaferin-A Inhibits Colon Cancer Cell Growth by blocking STAT3 Transcriptional Activity. J Cancer Prev 2015;20(3):185-92.
9. Mishra LC, Singh BB, Dagenais S. Scientific Basis for the Therapeutic Use of Withania somnifera (Ashwagandha): A Review. Altern Med Rev 2000;5(4):334-46.
10. Singh G, Sharma PK, Dudhe R and Singh S. Biological activities of Withania somnifera. Annals Biol Res 2010;1(3):56-63.
11. Muralikrishnan G, Dinda AK, Shakeel F. Immunomodulatory effects of Withania somnifera on azoxymethane induced experimental colon cancer in mice. Immunol Invest 2010;39(7):688-98.
12. Muralikrishnan G, Amanullah S, Basha MI, Dinda AK, Shakeel F. Modulating effect of Withania somnifera on TCA cycle enzymes and electron transport chain in azoxymethane-inducedcolon cancer in mice. Immunopharmacol Immunotoxicol 2010;32(3):523-527.
13. Yadav B, Bajaj A, Saxena M, Saxena AK. In Vitro Anticancer Activity of the Root, Stem and Leaves of Withania Somnifera against Various Human Cancer Cell Lines. Indian J Pharm Sci 2010;72(5):659- 63.
14. Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther 2010;9(1):202-10.
15. Das T, Roy KS, Chakrabarti T, Mukhopadhyay S, Roychoudhury S. Withaferin A modulates the Spindle Assembly Checkpoint by degradation of Mad2-Cdc20 complex in colorectal cancer cell lines. Biochem Pharmacol 2014;91(1):31-9.
16.Malik F, Kumar A, Bhushan S, Khan S, Bhatia A, Suri KA et al. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine. Apoptosis 2007;12(11):2115-33.
17.Mondal S, Mandal C, Sangwan R, Chandra S, Mandal C. Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Mol Cancer 2010;9:239.
18.Senthil V, Ramadevi S, Venkatakrishnan V, Giridharan P,Lakshmi BS, Vishwakarma RA et al. Withanolide induces apoptosis in HL-60 leukemia cells via mitochondria mediated cytochrome c release and caspase activation. Chem Biol Interact 2007;167(1):19-30.
19.Turrini E, Calcabrini C, Sestili P, Catanzaro E, Gianni ED, Diaz AR,et al. Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells. Toxins 2016;8(5):147.
20. Senthilnathan P, Padmavathi R, Banu SM, Sakthisekaran D. Enhancement of antitumor effect of paclitaxel in combination with immunomodulatory Withania somnifera on benzo(a) pyrene induced experimental lung cancer. Chem Biol Interact 2016;159(3):180-5.
21. Choudhary MI, Hussain S, Yousuf S, Dar A, Mudassar, Atta-ur- Rahman. Chlorinated and diepoxy withanolides from Withania somnifera and their cytotoxic effects against human lung cancer cell line. Phytochemistry 2010;71(17-18):2205-9.
22. Liu X, Chen L, Liang T, Tian XD, Liu Y, Zhang T. Withaferin A induces mitochondrial-dependent apoptosis in non-small cell lung cancer cells via generation of reactive oxygen species. J BUON 2017;22(1):244-50.
23. Singh N, Singh SP, Nath R, Singh DR, Gupta ML, Kohli RP, Bhargava KP. Prevention of urethane induced Lung adenomas by Withania somnifera (L) Dunal in albino mice. Int J of Crude Res 1986; 24(2):90-100.
24. Padmavathi B, Rath PC, Rao AR, Singh RP. Roots of withania somnifera inhibit forestomach and skin carcinogenesis in mice. Evid Based Complement Alternat Med 2005;2(1):99-105.
25. Mathur S, Kaur P, Sharma M, Katyal A, Singh B, Tiwari M, et al. The treatment of skin carcinoma, induced by UV B radiation, using 1-oxo-5beta, 6beta-epoxy-witha-2-enolide, isolated from the roots of Withania somnifera, in a rat model. Phytomedicine 2004;11(5):452-60.
26. Prakash J, Gupta SK, Dinda AK. Withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in Swiss albino mice. Nutr Cancer 2002;42(1):91-7.
27. Li W, Zhang C, Du H, Huang V, Sun B, Harris JP, et al. Withaferin A Suppresses the Up-Regulation of Acetyl-CoA Carboxylase 1 and Skin Tumor Formation in a Skin Carcinogenesis Mouse Model. Mol Carcinog 2016;55(11):1739-46.
28. Li W, Zhao Y. Withaferin A suppresses tumor promoter 12-O-tetradecanoylphorbol 13-acetate-induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells. Cancer Sci 2013;104(2):143-8.
29. Yang ES, Choi MJ, Kim JH, Choi KS, Kwon TK. Withaferin A enhances radiation-induced apoptosis in Caki cells through induction of reactive oxygen species, Bcl-2 downregulation and Akt inhibition. Chem Biol Interact 2011;190(1):9-15.
30. Um HJ, Min KJ, Kim DE, Kwon TK. Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun 2012;427(1):24-9.
31. Choi MJ, Park EJ, Min KJ, Park JW, Kwon TK. Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells. Toxicol In Vitro 2011;25(3):692-98.
32. Xu YM, Brooks AD, Wijeratne EM, Henrich CJ, Tewary P, Sayers TJ, et al. 17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor‑α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis: Structure−Activity Relationships. J Med Chem 2017;60(7):3039-51.
33. Roy RV, Suman S, Das TP, Luevano JE, Damodaran C. Withaferin-A induces mitotic catastrophe and growth arrest in prostate cancer cells. J Nat Prod 2013;76(10):1909-15.
34. Aalinkeel R, Hu Z, Nair BB, Sykes DE, Reynolds JL, Mahajan SD, et al. Genomic Analysis Highlights the Role of the JAK-STAT Signaling in the Anti-proliferative Effects of Dietary Flavonoid—‘Ashwagandha’ in Prostate Cancer Cells. Evid Based Complement Alternat Med 2010;7(2):177-87.
35. Nishikawa Y, Okuzaki D, Fukushima K, Mukai S, Ohno S, Ozaki Y, et al. WithaferinA Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells. PLoS ONE 2015;10(7):e0134137.
36. Srinivasan S, Ranga RS, Burikhanov R, Han SS, Chendil D. Par-4–Dependent Apoptosis by the Dietary Compound Withaferin A in Prostate Cancer Cells. Cancer Res 2007;67(1):246-53.
37. Li X, Zhu F, Jiang J, Sun C, Zhong Q, Shen M, et al. Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells. Autophagy 2016;12(9):1521-37.
38. Li X, Zhu F, Jiang J, Sun C, Wang X, Shen M, et al. Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells. Cancer Lett 2015;357(1):219-30.
39. Yu Y, Hamza A, Zhang T, Gu M, Zou P, Newman B, et al. Withaferin A Targets Heat Shock Protein 90 in Pancreatic Cancer Cells. Biochem Pharmacol 2010;79(4):542-51.
40. Sarkar S, Mandal C, Sangwan R, Mandal C. Coupling G2/M arrest to the Wnt/ β-catenin pathway restrains pancreatic adenocarcinoma. Endocr Relat Cancer 2014;21(1):113-25.
41. Davis L, Kuttan G. Effect of Withania somnifera on 20-methylcholanthrene induced fibrosarcoma. J Exp Clin Cancer Res 2000;19(2):165-7.
42. Prakash J, Gupta SK, Kochupillai V, Singh N, Gupta YK, Joshi S. Chemopreventive activity of Withania somnifera in experimentally induced fibrosarcoma tumours in Swiss albino mice. Phytother Res 2001;15(3):240-44.
43. Kaileh M, Vanden Berghe W, Boone E, Essawi T, Haegeman G. Screening of indigenous Palestinian medicinal plants for potential anti-inflammatory and cytotoxic activity. J Ethnopharmacol 2007; 113(3):510-16.
44. Mayola E, Gallerne C, Esposti DD, Martel C, Pervaiz S, Larue L, et al. Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2. Apoptosis 2011;16(10):1014-27.
45. Kalthur G, Mutalik S, Pathirissery UD. Effect of Withaferin A on the Development and Decay of Thermotolerance in B16F1 Melanoma: A Preliminary Study. Integr Cancer Ther 2009;8(1):93-7.
46. Halder B, Singh S, Thakur SS. Withania somnifera Root Extract Has Potent Cytotoxic Effect against Human Malignant Melanoma Cells. PLoS ONE 2015;10(9):e0137498.
47. Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis 2011;32(11):1697-705.
48. Jha AK, Nikbakht M, Capalash N, Kaur J. Demethylation of RARβ2 Gene Promoter by Withania somnifera in HeLa Cell Line. European J Med Plants 2014;4(5):503-10.
49. Lee DH, Lim IH, Sung EG, Kim JY, Song IH, Park YK, et al. Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway. Oncol Rep 2013;30(2):933-8.
50. Li AX, Sun M, Li X. Withaferin-A induces apoptosis in osteosarcoma U2OS cell line via generation of ROS and disruption of mitochondrial membrane pote
ntial. Eur Rev Med Pharmacol Sci 2017;21(6):1368-74.
51. Lv TZ, Wang GS. Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins. Exp Ther Med 2015;10(1):323-29.
52. Yang Z, Garcia A, Xu S, Powell DR, Vertino PM, Singh S, et al. Withania somnifera Root Extract Inhibits Mammary Cancer Metastasis and Epithelial to Mesenchymal Transition. PLoS ONE 2013;8(9):e75069.
53. Lee J, Hahm ER, Marcus AI, Singh SV. Withaferin A inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol Carcinog 2015;54(6):417-29.
54. Hahm ER, Lee J, Singh SV. Role of mitogen-activated protein kinases and Mcl-1 in apoptosis induction by withaferin A in human breast cancer cells. Mol Carcinog 2014;53(11):907-16.
55. Lee J, Sehrawat A, Singh SV. Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast Cancer Res Treat 2012;136(1):45-56.
56. Hahm ER, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is associated with suppression of inhibitor of apoptosis family protein expression. Cancer Lett 2013;334(1):101-8.
57. Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A Causes FOXO3a- and Bim-Dependent Apoptosis and Inhibits Growth of Human Breast Cancer Cells In vivo. Cancer Res 2008;68(18):7661-9.
58. Srivastava AN, Ahmad R, Khan MA. Evaluation and comparison of the in vitro cytotoxic activity of withania somnifera methanolic and ethanolic extracts against MDA-MB-231 and Vero cell lines. Sci Pharm 2015;84(1):41-59.
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Published
2018-01-25
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Section
Review Articles
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