Skip to main content

Molecular Targets and Mechanisms of Cancer Prevention and Treatment by Withaferin A, A Naturally Occurring Steroidal Lactone

Abstract

The plants used in Ayurvedic medicine, which has been practiced in India for thousands of years for the treatment of a variety of disorders, are rich in chemicals potentially useful for prevention and treatment of cancer. Withania somnifera (commonly known as Ashwagandha in Ayurvedic medicine) is one such medicinal plant whose anticancer value was realized over four decades ago after isolation of a crystalline steroidal compound (withaferin A) from the leaves of this shrub. The root and leaf extracts of W. somnifera are shown to confer protection against chemically-induced cancers in experimental rodents, and retard tumor xenograft growth in athymic mice. Anticancer effect of W. somnifera is generally attributable to steroidal lactones collectively referred to as withanolides. Withaferin A (WA) appears most active against cancer among structurally divergent withanolides isolated from the root or leaf of W. somnifera. Cancer-protective role for WA has now been established using chemically-induced and oncogene-driven rodent cancer models. This review summarizes the key in vivo preclinical studies demonstrating anticancer effects of WA. Molecular targets and mechanisms likely contributing to the anticancer effects of WA are also discussed. Finally, challenges in clinical development of WA for the prevention and treatment of cancer are highlighted.

This is a preview of subscription content, access via your institution.

Fig. 1

REFERENCES

  1. Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981–2002. J Nat Prod. 2003;66(7):1022–37.

    CAS  PubMed  Google Scholar 

  2. Pezzuto JM, Kosmeder II JW, Park EJ, Lee SK, Cuendet M, Gills J, et al. Characterization of natural product cancer chemopreventive agents. In: Kelloff GJ, Hawk ET, Sigman CC, editors. Cancer chemoprevention, vol. 2. Strategies for cancer chemoprevention. Totowa, NJ: Humana Press; 2005. p. 3–37.

    Google Scholar 

  3. Garodia P, Ichikawa H, Malani N, Sethi G, Aggarwal BB. From ancient medicine to modern medicine: ayurvedic concepts of health and their role in inflammation and cancer. J Soc Integr Oncol. 2007;5(1):25–37.

    PubMed  Google Scholar 

  4. Mirjalili MH, Moyano E, Bonfill M, Cusido RM, Palazón J. Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules. 2009;14(7):2373–93.

    CAS  PubMed  Google Scholar 

  5. 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.

    CAS  PubMed  Google Scholar 

  6. Winters M. Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology. Altern Med Rev. 2006;11(4):269–77.

    PubMed  Google Scholar 

  7. Shohat B, Gitter S, Abraham A, Lavie D. Antitumor activity of withaferin A (NSC-101088). Cancer Chemother Rep. 1967;51(5):271–6.

    CAS  PubMed  Google Scholar 

  8. Davis L, Kuttan G. Effect of Withania somnifera on 20-methylcholanthrene induced fibrosarcoma. J Exp Clin Cancer Res. 2000;19(2):165–7.

    CAS  PubMed  Google Scholar 

  9. Davis L, Kuttan G. Effect of Withania somnifera on DMBA induced carcinogenesis. J Ethnopharmacol. 2001;75(2–3):165–8.

    CAS  PubMed  Google Scholar 

  10. 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):240–4.

    CAS  PubMed  Google Scholar 

  11. 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.

    PubMed  Google Scholar 

  12. 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.

    PubMed Central  PubMed  Google Scholar 

  13. Khazal KF, Samuel T, Hill DL, Grubbs CJ. Effect of an extract of Withania somnifera root on estrogen receptor-positive mammary carcinomas. Anticancer Res. 2013;33(4):1519–23.

    PubMed  Google Scholar 

  14. Devi PU, Sharada AC, Solomon FE, Kamath MS. In vivo growth inhibitory effect of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma 180. Indian J Exp Biol. 1992;30(3):169–72.

    CAS  PubMed  Google Scholar 

  15. Devi PU, Sharada AC, Solomon FE. Antitumor and radiosensitizing effects of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma-180. Indian J Exp Biol. 1993;31(7):607–11.

    CAS  PubMed  Google Scholar 

  16. Christina AJM, Joseph DG, Packialakshmi M, Kothai R, Robert SJH, Chidambaranathan N, et al. Anticarcinogenic activity of Withania somnifera Dunal against Dalton’s ascitic lymphoma. J Ethnopharmacol. 2004;93(2–3):359–61.

    CAS  PubMed  Google Scholar 

  17. Leyon PV, Kuttan G. Effect of Withania somnifera on B16F-10 melanoma induced metastasis in mice. Phytother Res. 2004;18(2):118–22.

    CAS  PubMed  Google Scholar 

  18. Widodo N, Kaur K, Shrestha BG, Takagi Y, Ishii T, Wadhwa R, et al. Selective killing of cancer cells by leaf extract of Ashwagandha: identification of a tumor-inhibitory factor and the first molecular insights to its effect. Clin Cancer Res. 2007;13(7):2298–306.

    CAS  PubMed  Google Scholar 

  19. Hamza A, Amin A, Daoud S. The protective effect of a purified extract of Withania somnifera against doxorubicin-induced cardiac toxicity in rats. Cell Biol Toxicol. 2008;24(1):63–73.

    CAS  PubMed  Google Scholar 

  20. Biswal BM, Sulaiman SA, Ismail HC, Zakaria H, Musa KI. Effect of Withania somnifera (Ashwagandha) on the development of chemotherapy-induced fatigue and quality of life in breast cancer patients. Integr Cancer Ther. 2013;12(4):312–22.

    CAS  PubMed  Google Scholar 

  21. Jayaprakasam B, Zhang Y, Seeram NP, Nair MG. Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life Sci. 2003;74(1):125–32.

    CAS  PubMed  Google Scholar 

  22. Ichikawa H, Takada Y, Shishodia S, Jayaprakasam B, Nair MG, Aggarwal BB. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-κB (NF-κB) activation and NF-κB-regulated gene expression. Mol Cancer Ther. 2006;5(6):1434–45.

    CAS  PubMed  Google Scholar 

  23. Shohat B, Shaltiel A, Ben-Bassat M, Joshua H. The effect of withaferin A, a natural steroidal lactone, on the fine structure of S-180 tumor cells. Cancer Lett. 1976;2(2):71–8.

    CAS  PubMed  Google Scholar 

  24. Devi PU, Sharada AC, Solomon FE. In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma. Cancer Lett. 1995;95(1–2):189–93.

    CAS  PubMed  Google Scholar 

  25. Devi PU, Kamath R, Rao BS. Radiosensitization of a mouse melanoma by withaferin A: in vivo studies. Indian J Exp Biol. 2000;38(5):432–7.

    CAS  PubMed  Google Scholar 

  26. Devi PU, Kamath R. Radiosensitizing effect of withaferin A combined with hyperthermia on mouse fibrosarcoma and melanoma. J Radiat Res. 2003;44(1):1–6.

    CAS  Google Scholar 

  27. Yang H, Shi G, Dou QP. The tumor proteasome is a primary target for the natural anticancer compound Withaferin A isolated from "Indian winter cherry". Mol Pharmacol. 2007;71(2):426–37.

    CAS  PubMed  Google Scholar 

  28. 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.

    CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Samadi AK, Mukerji R, Shah A, Timmermann BN, Cohen MS. A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo. Surgery. 2010;148(6):1228–36.

    PubMed Central  PubMed  Google Scholar 

  31. Lahat G, Zhu QS, Huang KL, Wang S, Bolshakov S, Liu J, et al. Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies. PLoS One. 2010;5(4):e10105.

    PubMed Central  PubMed  Google Scholar 

  32. Thaiparambil JT, Bender L, Ganesh T, Kline E, Patel P, Liu Y, et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer. 2011;129(11):2744–55.

    CAS  PubMed  Google Scholar 

  33. 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.

    CAS  PubMed  Google Scholar 

  34. Samadi AK, Cohen SM, Mukerji R, Chaguturu V, Zhang X, Timmermann BN, et al. Natural withanolide withaferin A induces apoptosis in uveal melanoma cells by suppression of Akt and c-MET activation. Tumor Biol. 2012;33(4):1179–89.

    CAS  Google Scholar 

  35. Yang H, Wang Y, Cheryan VT, Wu W, Cui CQ, Polin LA, et al. Withaferin A inhibits the proteasome activity in mesothelioma in vitro and in vivo. PLoS One. 2012;7(8):e41214.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Manoharan S, Panjamurthy K, Menon VP, Balakrishnan S, Alias LM. Protective effect of Withaferin-A on tumour formation in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis in hamsters. Indian J Exp Biol. 2009;47(1):16–23.

    CAS  PubMed  Google Scholar 

  38. Panjamurthy K, Manoharan S, Nirmal MR, Vellaichamy L. Protective role of Withaferin-A on immunoexpression of p53 and bcl-2 in 7,12-dimethylbenz(a)anthracene-induced experimental oral carcinogenesis. Invest New Drugs. 2009;27(5):447–52.

    CAS  PubMed  Google Scholar 

  39. Manoharan S, Panjamurthy K, Balakrishnan S, Vasudevan K, Vellaichamy L. Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis. Pharmacol Rep. 2009;61(4):719–26.

    CAS  PubMed  Google Scholar 

  40. Hahm ER, Lee J, Kim SH, Sehrawat A, Arlotti JA, Shiva SS, et al. Metabolic alterations in mammary cancer prevention by withaferin A in a clinically relevant mouse model. J Natl Cancer Inst. 2013;105(15):1111–22.

    CAS  PubMed  Google Scholar 

  41. Patil D, Gautam M, Mishra S, Karupothula S, Gairola S, Jadhav S, et al. Determination of withaferin A and withanolide A in mice plasma using high-performance liquid chromatography-tandem mass spectrometry: application to pharmacokinetics after oral administration of Withania somnifera aqueous extract. J Pharm Biomed Anal. 2013;80:203–12.

    CAS  PubMed  Google Scholar 

  42. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    CAS  PubMed  Google Scholar 

  43. Stan SD, Zeng Y, Singh SV. Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells. Nutr Cancer. 2008;60 Suppl 1:51–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Zhang X, Mukerji R, Samadi AK, Cohen MS. Down-regulation of estrogen receptor-alpha and rearranged during transfection tyrosine kinase is associated with withaferin A-induced apoptosis in MCF-7 breast cancer cells. BMC Complement Altern Med. 2011;11:84.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Samadi AK, Tong X, Mukerji R, Zhang H, Timmermann BN, Cohen MS. Withaferin A, a cytotoxic steroid from Vassobia breviflora, induces apoptosis in human head and neck squamous cell carcinoma. J Nat Prod. 2010;73(9):1476–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Shah N, Kataria H, Kaul SC, Ishii T, Kaur G, Wadhwa R. Effect of the alcoholic extract of Ashwagandha leaves and its components on proliferation, migration, and differentiation of glioblastoma cells: combinational approach for enhanced differentiation. Cancer Sci. 2009;100(9):1740–7.

    CAS  PubMed  Google Scholar 

  47. Grogan PT, Sleder KD, Samadi AK, Zhang H, Timmermann BN, Cohen MS. Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways. Invest New Drugs. 2013;31(3):545–57.

    CAS  PubMed  Google Scholar 

  48. Zhang X, Samadi AK, Roby KF, Timmermann B, Cohen MS. Inhibition of cell growth and induction of apoptosis in ovarian carcinoma cell lines CaOV3 and SKOV3 by natural withanolide Withaferin A. Gynecol Oncol. 2012;124(3):606–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Cohen SM, Mukerji R, Timmermann BN, Samadi AK, Cohen MS. A novel combination of withaferin A and sorafenib shows synergistic efficacy against both papillary and anaplastic thyroid cancers. Am J Surg. 2012;204(6):895–900.

    CAS  PubMed  Google Scholar 

  50. Sen N, Banerjee B, Das BB, Ganguly A, Sen T, Pramanik S, et al. Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex. Cell Death Differ. 2007;14(2):358–67.

    CAS  PubMed  Google Scholar 

  51. Hahm ER, Moura MB, Kelley EE, Van Houten B, Shiva S, Singh SV. Withaferin A-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species. PLoS One. 2011;6(8):e23354.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. 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.

    CAS  Google Scholar 

  53. 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.

    CAS  PubMed  Google Scholar 

  54. Oh JH, Lee TJ, Kim SH, Choi YH, Lee SH, Lee JM, et al. Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation. Apoptosis. 2008;13(12):1494–504.

    CAS  PubMed  Google Scholar 

  55. Mandal C, Dutta A, Mallick A, Chandra S, Misra L, Sangwan RS, et al. Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. Apoptosis. 2008;13(12):1450–64.

    CAS  PubMed  Google Scholar 

  56. Mehrotra A, Kaul D, Joshi K. LXR-α selectively reprogrammes cancer cells to enter into apoptosis. Mol Cell Biochem. 2011;349(1–2):41–55.

    CAS  PubMed  Google Scholar 

  57. 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):692–8.

    CAS  PubMed  Google Scholar 

  58. 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.

    CAS  PubMed  Google Scholar 

  59. Widodo N, Priyandoko D, Shah N, Wadhwa R, Kaul SC. Selective killing of cancer cells by Ashwagandha leaf extract and its component withanone involves ROS signaling. PLoS One. 2010;5(10):e13536.

    PubMed Central  PubMed  Google Scholar 

  60. Lee TJ, Um HJ, Do Min S, Park JW, Choi KS, Kwon TK. Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP. Free Radic Biol Med. 2009;46(12):1639–49.

    CAS  PubMed  Google Scholar 

  61. 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.

    CAS  PubMed  Google Scholar 

  62. Fuska J, Fusková A, Rosazza JP, Nicholas AW. Novel cytotoxic and antitumor agents. IV. Withaferin A: relation of its structure to the in vitro cytotoxic effects on P388 cells. Neoplasma. 1984;31(1):31–6.

    CAS  PubMed  Google Scholar 

  63. Jilani K, Lupescu A, Zbidah M, Shaik N, Lang F. Withaferin A-stimulated Ca2+ entry, ceramide formation and suicidal death of erythrocytes. Toxicol In Vitro. 2013;27(1):52–8.

    CAS  PubMed  Google Scholar 

  64. Raina A, Kaul D. LXR-α genomics programmes neuronal death observed in Alzheimer’s disease. Apoptosis. 2010;15(12):1461–9.

    CAS  PubMed  Google Scholar 

  65. Franchitto A, Torrice A, Semeraro R, Napoli C, Nuzzo G, Giuliante F, et al. Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down-regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically. Am J Pathol. 2010;177(4):1779–90.

    CAS  PubMed  Google Scholar 

  66. Mohan R, Hammers HJ, Bargagna-Mohan P, Zhan XH, Herbstritt CJ, Ruiz A, et al. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis. 2004;7(2):115–22.

    CAS  PubMed  Google Scholar 

  67. Grover A, Shandilya A, Bisaria VS, Sundar D. Probing the anticancer mechanism of prospective herbal drug Withaferin A on mammals: a case study on human and bovine proteasomes. BMC Genomics. 2010;11 Suppl 4:S15.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer. 2002;2(8):594–604.

    CAS  PubMed  Google Scholar 

  70. Hahm ER, Lee J, Huang Y, Singh SV. Withaferin A suppresses estrogen receptor-α expression in human breast cancer cells. Mol Carcinog. 2011;50(8):614–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 1998;17(25):3247–59.

    PubMed  Google Scholar 

  72. Deveraux QL, Reed JC. IAP family proteins—suppressors of apoptosis. Genes Dev. 1999;13(3):239–52.

    CAS  PubMed  Google Scholar 

  73. Wadegaonkar VP, Wadegaonkar PA. Withaferin A targets apoptosis inhibitor cIAP1: a potential anticancer candidate. J Appl Pharm Sci. 2012;2(5):154–7.

    Google Scholar 

  74. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90.

    CAS  PubMed  Google Scholar 

  75. Dhanasekaran DN, Johnson GL. MAPKs: function, regulation, role in cancer and therapeutic targeting. Oncogene. 2007;26(22):3097–9.

    CAS  PubMed  Google Scholar 

  76. Hahm E, 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. 2013 (in press).

  77. Karin M, Cao Y, Greten FR, Li ZW. NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2(4):301–10.

    CAS  PubMed  Google Scholar 

  78. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.

    CAS  PubMed  Google Scholar 

  79. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.

    CAS  PubMed  Google Scholar 

  80. Lee J, Hahm ER, Singh SV. Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells. Carcinogenesis. 2010;31(11):1991–8.

    CAS  PubMed  Google Scholar 

  81. 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.

    CAS  PubMed  Google Scholar 

  82. Ali S, Coombes RC. Estrogen receptor alpha in human breast cancer: occurrence and significance. J Mammary Gland Biol Neoplasia. 2000;5(3):271–81.

    CAS  PubMed  Google Scholar 

  83. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006;107(6):2223–33.

    CAS  PubMed  Google Scholar 

  84. Mumm JS, Kopan R. Notch signaling: from the outside in. Dev Biol. 2000;228(2):151–65.

    CAS  PubMed  Google Scholar 

  85. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Su M, Mei Y, Sinha S. Role of the crosstalk between autophagy and apoptosis in cancer. J Oncol. 2013;2013:102735.

    PubMed Central  PubMed  Google Scholar 

  88. Herman-Antosiewicz A, Johnson DE, Singh SV. Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res. 2006;66(11):5828–35.

    CAS  PubMed  Google Scholar 

  89. Bommareddy A, Hahm ER, Xiao D, Powolny AA, Fisher AL, Jiang Y, et al. Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells. Cancer Res. 2009;69(8):3704–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Hahm ER, Singh SV. Autophagy fails to alter withaferin A-mediated lethality in human breast cancer cells. Curr Cancer Drug Targets. 2013;13(6):640–50.

    CAS  PubMed  Google Scholar 

  91. Fong MY, Jin S, Rane M, Singh RK, Gupta R, Kakar SS. Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer. PLoS One. 2012;7(7):e42265.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Kakar SS, Jala VR, Fong MY. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem Biophys Res Commun. 2012;423(4):819–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Suttana W, Mankhetkorn S, Poompimon W, Palagani A, Zhokhov S, Gerlo S, et al. Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols. Mol Cancer. 2010;9:99.

    PubMed Central  PubMed  Google Scholar 

  94. Yang ES, Choi MJ, Kim JH, Choi KS, Kwon TK. Combination of withaferin A and X-ray irradiation enhances apoptosis in U937 cells. Toxicol in Vitro. 2011;25(8):1803–10.

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The work cited in this article from the authors’ laboratory was supported by the United States Public Health Service Grant CA142604-04 (to SVS).

Conflict of Interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shivendra V. Singh.

Additional information

Guest Editors: Ah-Ng Tony Kong and Chi Chen

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vyas, A.R., Singh, S.V. Molecular Targets and Mechanisms of Cancer Prevention and Treatment by Withaferin A, A Naturally Occurring Steroidal Lactone. AAPS J 16, 1–10 (2014). https://doi.org/10.1208/s12248-013-9531-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-013-9531-1

KEY WORDS

  • apoptosis
  • autophagy
  • cell cycle
  • chemoprevention
  • signal transduction
  • withaferin A