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Withaferin A

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Withaferin A
Names
IUPAC name
(4β,5β,6β,22R)-4,27-Dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione
Other names
Withaferine A
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
  • InChI=1S/C28H38O6/c1-14-11-21(33-25(32)17(14)13-29)15(2)18-5-6-19-16-12-24-28(34-24)23(31)8-7-22(30)27(28,4)20(16)9-10-26(18,19)3/h7-8,15-16,18-21,23-24,29,31H,5-6,9-13H2,1-4H3/t15-,16-,18+,19-,20-,21+,23-,24+,26+,27-,28+/m0/s1
    Key: DBRXOUCRJQVYJQ-CKNDUULBSA-N
  • InChI=1/C28H38O6/c1-14-11-21(33-25(32)17(14)13-29)15(2)18-5-6-19-16-12-24-28(34-24)23(31)8-7-22(30)27(28,4)20(16)9-10-26(18,19)3/h7-8,15-16,18-21,23-24,29,31H,5-6,9-13H2,1-4H3/t15-,16-,18+,19-,20-,21+,23-,24+,26+,27-,28+/m0/s1
    Key: DBRXOUCRJQVYJQ-CKNDUULBBI
  • O=C/1O[C@H](CC(=C\1CO)\C)[C@@H](C)[C@H]6CC[C@@H]4[C@]6(C)CC[C@@H]3[C@]5(C(=O)\C=C/[C@H](O)[C@]52O[C@@H]2C[C@H]34)C
Properties
C28H38O6
Molar mass 470.606 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Withaferin A is a steroidal lactone, derived from Acnistus arborescens,[1] Withania somnifera[2] (Indian Winter cherry or Ashwagandha in Sanskrit) and other members of Solanaceae family. It has been traditionally used in the ayurvedic medicine. It is the first member of the withanolide class of ergostane type product to be discovered. This natural product has wide range of pharmacological activities including cardioprotective, anti-inflammatory, immuno-modulatory, anti-angiogenesis,[2] anti-metastasis and anti-carcinogenic properties.

Structure

Withanolides are a group of naturally occurring C28- steroidal lactones. They contain four cycloalkane ring structures, three cyclohexane rings and one cyclopentane ring.[3] Withaferin A is highly reactive because of the ketone containing unsaturated A ring, the epoxide in B ring and unsaturated lactone ring. The double bond in ring A and the epoxide ring are mainly responsible for the cytotoxicity. The 22nd and 26th carbon of ergostane skeleton in withaferin A and related steroidal compounds are oxidized to form six membered delta lactone unit. NMR spectral analysis identifies C3 in the unsaturated A ring as the main nucleophilic target site for ethyl mercaptan, thiophenol and L-cysteine ethyl ester in vitro.[3] A library of 2, 3-dihydro-3β-substituted derivatives are synthesized by regio/stereoselective Michael addition to ring A. These analogs are tested for its activity in neuro-degenerative diseases, autoimmune and inflammatory diseases and in cancer.

Regulation

3-azido Withaferin A (3-azidoWA), a stable derivative of withaferin A, has been shown to inhibit cancer cell motility and invasion in wound healing by selectively suppressing MMP-2 activity in human cervical and prostate cell lines.[4] It enhances the secretion of Par-4 which in turn suppresses MMP-2 expression and activity that is required for tumor metastasis. 3-azidoWA acts as a tumor suppressor by inducing Par-4, TIMP-1 and by reducing the levels of pAkt and pERK that are activated in various cancers. This finding has augmented the therapeutic potential of the pro-apoptotic protein Par-4 in cancer. Researchers have shown that 3-azidoWA abrogated neovascularisation in vivo in a dose dependent manner.[4]

Withaferin A has been shown to inhibit cell proliferation in HUVECs at significantly lower doses through the inhibition of Cyclin D1 expression.[2] Inhibition of cell proliferation is due to the cytostatic nature of withaferin, resulting in cell arrest in G0G1 phase of cell cycle. Researchers have shown that withaferin A has an anti-angiogenic activity in vivo at doses much lower than required for its anti-tumor activity.[2]

Regulation of transcription factor NF-κB

NF-κB is a transcription factor that regulates many genes involved in cell survival, growth, immune response and angiogenesis. Withaferin A inhibits NF-κB at a very low concentration by targeting the ubiquitin-mediated proteasome pathway (UPP) in endothelial cells.[2] Scientists believe that the site at which withaferin acts on UPP must be different from the site of action of 20s proteasome inhibitor. In vitro experiments demonstrated that withaferin A interferes with TNF-induced NF-κB activation at the level or upstream of IKKβ.[5] It also inhibits other transcription factors including Ap1[6] and Sp1[7] which are important mediators of many signalling pathways that are down-regulated by various chemotherapeutic agents. It can induce oxidative stress, alter gene expression, depolarize mitochondria. Withaferin A also down regulates VEGF gene expression[7] and can affect calcium signaling.[8] Mohan et al. [2] showed that withaferin A could inhibit endothelial cell proliferation at low concentrations and thus non-toxic to cells.

Regulation of heat shock proteins

Researchers have demonstrated the regulation of Hsp90 co-chaperone CDC37 through direct irreversible binding of withaferin A to C-terminus of Hsp90.[9] Withaferin induces aggregation of Hsp90, dissociation of Hsp90- CDC37 complex and down regulation of Hsp90 target proteins mediated through proteasomal degradation. Induction of heat shock response by withaferin provides cytoprotective property whereas inhibition of heat shock protein activity will lead to apoptosis. This dual property of withaferin on heat shock protein might be due to the concentration of withaferin and cellular content.

Properties

Anti-inflammatory

Withania extracts suppresses the production of various pro-inflammatory molecules in many in vitro models. Anti-inflammatory property of withaferin A has been attributed to its ability to suppress alpha-2 macroglobulin, NF-κB and AP1.[6] Several withanolides selective inhibition of enzyme cyclooxygenase-2 (COX-2) that increases during inflammation.[6]

Anti-tumor

The anti-tumor activity of withaferin A was tested on human prostate cancer cell line, PC-3 and confirmed in PC-3 xenografts in nude mice. It exhibits androgen receptor (AR) dependent cytotoxicity. It inhibits tumor growth through ATP- independent inhibition of heat shock protein 90 (HSP90) in in vivo pancreatic model.[9] It exhibits growth- inhibitory properties in cancer cell culture experiments, suggesting its cytotoxic and apoptotic properties. It increases Mcl-1 expression levels inducing apoptosis in vitro breast cancer models. It binds to intermediate filament protein, vimentin by covalently modifying its highly conserved cysteine residue in alpha-helical colied 2B domain.[10] Withaferin A causes aggregation of vimentin to colocalize with F-actin leading to apoptosis.

Immunosuppressive

Shohat et al., have demonstrated specific immunosuppressive effects on mouse thymocytes as well as human B and T lymphocytes by withaferin A and a related steroid lactone withanolide E.[11] At very low concentrations, these molecules inhibit the E rosette and EAC rosette formation by normal B and T lymphocytes. Withaferin A has a specific action on antigen recognition and proliferative capacity of both B and T lymphocytes.[2]

Cell motility and invasion

Withaferin A inhibits cell motility and invasion capacity of cancer cells through MMP-2 by induction of Par-4.[4] Since a critical event in cancer metastasis is the ability of these cells to invade the extracellular matrix (ECM), inhibition of invasive property by withaferin can contain the cancer cells to primary site. Colony forming ability of cancer cells were attenuated by withaferin derivative in a dose dependent manner.[4]Actin is required for various cellular processes including oriented growth, adhesion and migration. Withaferin A can alter cytoskeleton architecture by covalently binding to multifunctional adaptor protein annexin II and by stimulating the basal F-actin cross linking activity.[12]

Anti-angiogenesis

It is a potent inhibitor of angiogenesis.[10] Anti-angiogenic and anti-tumor activity of withaferin A is due to the inhibition of chymotrypsin whereas the induction of apoptosis is due to the inhibition of protein kinase C.[13] Caspase-3 activation by withaferin A has also been reported.

Clinical Relevance

Cancer

Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which inactivate the tumor suppressor protein p53 and pRb respectively. Withaferin A was found to down regulate expression of E6 and E7 oncoproteins, induce accumulation of p53, causes G2/M cell cycle arrest, alters the expression levels of apoptotic markers Bcl2, Bax and caspase3. In athymic mice model, withaferin reduced 70% of the tumor volume.[14] Therefore, withaferin A can be a potential therapeutic agent for the treatment of cervical cancer without major side effects. Withaferin A has been shown to enhance radiation-induced apoptosis in certain cell lines. However, it's mechanism of action on cell death is not well understood.[4] It has been suggested that sensitization of cancer cells to radiation is due to the inhibition of NF-κB. It exhibits anti-tumor as well as anti-inflammatory activities. It can act as an immuno-suppressant by inhibiting NF-κB activation. In animal models, it prevented skin cancer induced by ultraviolet radiation. The antioxidant property of withaferin aid in the prevention of DNA damage by mutagens; in combination with detoxifying, anti-inflammatory and immunomodulatory effects, it can contribute to the chemopreventive action.[6]

Withaferin A binds to and inhibits vimentin[10] preventing breast cancer cell growth both in vitro and in vivo. It increases the phosphorylation of JNK, ERK and MAPK in vitro breast cancer models. It increases the expression of tumor suppressor p53, Notch 2 and Notch 4, down-regulates the expression of ERα, resulting in the inhibition of cancer cell migration and growth. Notch signaling plays a significant role in the development of colon cancer, therefore targeting the Notch pathway by withaferin A can be a potential therapeutic option in treating colon cancer. Koduru et al., demonstrated that the inhibition of Notch- mediated prosurvival by withaferin A facilitates c-Jun-NH2-kinase-mediated apoptosis in colon cancer cell lines.[15] Withaferin A downregulates vimentin expression leading to structural perturbation of intermediary filaments. Cancer cells express enhanced vimentin expression and correlates with the induction of epithelial to mesenchymal transition (EMT), metastasis, poor prognosis and decreased survival rate. Further, caspase-dependent degradation of vimentin by withaferin A was observed. Combining various properties like anti-inflammatory, pro-apoptotic, anti-angiogenic and antiproliferation makes withaferin A a potential drug candidate for treatment of cancer. Studies in animal models has shown promising results for breast cancer,[16] pancreatic cancer,[9] cervical cancer,[17] lung cancer,[18] medullary thyroid cancer[19] among others.

Other diseases

Sen et al., have demonstrated that in Leishmania donovani, withaferin A inhibits PKC resulting in depolarization of Delta Psi(m) and generation of reactive oxygen species in the cell.[13] Depolarization leads to the release of cytochrome c and activation of caspase-likeprotease and DNA fragmentation, finally leading to apoptosis. Animal and in vitro studies have shown antibacterial effects against Staphylococcus aureus, Listeria monocytogenes, Bacillus anthracis, Bacillus subtilis, Salmonella enteridis and Salmonella typhimurium.[6] Withania roots have demonstrated chondroprotective effects in vitro arthritis model. The herb is also used in treatment of iron-deficiency anemia due to its effects on haematopoiesis and natural iron content.[6]

Interaction

Par-4[4]

Hsp90[9]

Vimentin[10]

NF-κB[2][5]

Annexin II[12]

Caspase-3[13]

p53[14]

See also

References

  1. ^ Kupchan, S. M.; Anderson, W. K.; Bollinger, P.; Doskotch, R. W.; Smith, R. M.; Renauld, J. A.; Schnoes, H. K.; Burlingame, A. L.; Smith, D. H. (1969-12-01). "Tumor inhibitors. XXXIX. Active principles of Acnistus arborescens. Isolation and structural and spectral studies of withaferin A and withacnistin". The Journal of Organic Chemistry. 34 (12): 3858–3866. ISSN 0022-3263. PMID 5357526.
  2. ^ a b c d e f g h Mohan, R; Hammers, HJ; Bargagna-Mohan, P; Zhan, XH; Herbstritt, CJ; Ruiz, A; Zhang, L; Hanson, AD; et al. (2004). "Withaferin A is a potent inhibitor of angiogenesis". Angiogenesis. 7 (2): 115–122. doi:10.1007/s10456-004-1026-3. PMID 15516832.
  3. ^ a b Vanden Berghe, Wim; Sabbe, Linde; Kaileh, Mary; Haegeman, Guy; Heyninck, Karen (2012-11-15). "Molecular insight in the multifunctional activities of Withaferin A". Biochemical Pharmacology. 84 (10): 1282–1291. doi:10.1016/j.bcp.2012.08.027. ISSN 1873-2968. PMID 22981382.
  4. ^ a b c d e f Rah, Bilal; Amin, Hina; Yousuf, Khalid; Khan, Sheema; Jamwal, Gayatri; Mukherjee, Debaraj; Goswami, Anindya. "A Novel MMP-2 Inhibitor 3-azidowithaferin A (3-azidoWA) Abrogates Cancer Cell Invasion and Angiogenesis by Modulating Extracellular Par-4". PLoS ONE. 7 (9). doi:10.1371/journal.pone.0044039. PMC 3433490. PMID 22962598.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ a b Kaileh, Mary; Vanden Berghe, Wim; Heyerick, Arne; Horion, Julie; Piette, Jacques; Libert, Claude; De Keukeleire, Denis; Essawi, Tamer; Haegeman, Guy (2007-02-16). "Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity". The Journal of Biological Chemistry. 282 (7): 4253–4264. doi:10.1074/jbc.M606728200. ISSN 0021-9258. PMID 17150968.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ a b c d e f Braun, Lesley; Cohen, Marc (2015-03-30). Herbs and Natural Supplements, Volume 2: An Evidence-Based Guide. Elsevier Health Sciences. ISBN 9780729581738.
  7. ^ a b Prasanna Kumar, S; Shilpa, P; Salimath Bharati, P (2009). "Withaferin A suppresses the expression of vascular endothelial growth factor in Ehrlich ascites tumor cells via Sp1 transcription factor". Current Trends in Biotechnology and Pharmacy. 3 (2): 138–148. ISSN 0973-8916.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Jilani, K.; Lupescu, A.; Zbidah, M.; Shaik, N.; Lang, F. (2013). "Withaferin A-stimulated Ca2+ entry, ceramide formation and suicidal death of erythrocytes". Toxicology in Vitro. 27 (1): 52–58. doi:10.1016/j.tiv.2012.09.004. PMID 22989414.
  9. ^ a b c d Yu, Yanke; Hamza, Adel; Zhang, Tao; Gu, Mancang; Zou, Peng; Newman, Bryan; Li, Yanyan; Gunatilaka, A. A. Leslie; Zhan, Chang-Guo (2010-02-15). "Withaferin A targets heat shock protein 90 in pancreatic cancer cells". Biochemical Pharmacology. 79 (4): 542–551. doi:10.1016/j.bcp.2009.09.017. ISSN 1873-2968. PMC 2794909. PMID 19769945.
  10. ^ a b c d Bargagna-Mohan, P.; Hamza, A.; Kim, Y. E.; Ho, Y. K.; Mor-Vaknin, N.; Wendschlag, N.; Liu, J.; Evans, R. M.; et al. (2007). "The tumor inhibitor and antiangiogenic agent Withaferin A targets the intermediate filament protein Vimentin". Chemistry & Biology. 14 (6): 623–634. doi:10.1016/j.chembiol.2007.04.010. PMC 3228641. PMID 17584610.
  11. ^ Shohat, B.; Kirson, I.; Lavie, D. (1978-02-01). "Immunosuppressive activity of two plant steroidal lactones withaferin A and withanolide E". Biomedicine / [publiée Pour l'A.A.I.C.I.G.] 28 (1): 18–24. ISSN 0300-0893. PMID 27256.
  12. ^ a b Falsey, Ryan R.; Marron, Marilyn T.; Gunaherath, G. M. Kamal B.; Shirahatti, Nikhil; Mahadevan, Daruka; Gunatilaka, A. A. Leslie; Whitesell, Luke (2006-01-01). "Actin microfilament aggregation induced by withaferin A is mediated by annexin II". Nature Chemical Biology. 2 (1): 33–38. doi:10.1038/nchembio755. ISSN 1552-4450. PMID 16408090.
  13. ^ a b c Sen, N.; Banerjee, B.; Das, B. B.; Ganguly, A.; Sen, T.; Pramanik, S.; Mukhopadhyay, S.; Majumder, H. K. (2006-07-14). "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 & Differentiation. 14 (2): 358–367. doi:10.1038/sj.cdd.4402002. ISSN 1350-9047.
  14. ^ a b Munagala, Radha; Kausar, Hina; Munjal, Charu; Gupta, Ramesh C. (2011-11-01). "Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells". Carcinogenesis. 32 (11): 1697–1705. doi:10.1093/carcin/bgr192. ISSN 0143-3334. PMID 21859835.
  15. ^ Koduru, Srinivas; Kumar, Raj; Srinivasan, Sowmyalakshmi; Evers, Mark B.; Damodaran, Chendil (2010-01-01). "Notch-1 Inhibition by Withaferin-A: A Therapeutic Target against Colon Carcinogenesis". Molecular Cancer Therapeutics. 9 (1): 202–210. doi:10.1158/1535-7163.MCT-09-0771. ISSN 1535-7163. PMC 3041017. PMID 20053782.
  16. ^ Thaiparambil, Jose T.; Bender, Laura; Ganesh, Thota; Kline, Erik; Patel, Pritty; Liu, Yuan; Tighiouart, Mourad; Vertino, Paula M.; Harvey, R. Donald (2011-12-01). "Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation". International Journal of Cancer. 129 (11): 2744–2755. doi:10.1002/ijc.25938. ISSN 1097-0215. PMID 21538350.
  17. ^ Munagala, Radha; Kausar, Hina; Munjal, Charu; Gupta, Ramesh C. (2011-11-01). "Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells". Carcinogenesis. 32 (11): 1697–1705. doi:10.1093/carcin/bgr192. ISSN 1460-2180. PMID 21859835.
  18. ^ Gupta, Ramesh C.; Bansal, Shyam S.; Aqil, Farrukh; Jeyabalan, Jeyaprakash; Cao, Pengxiao; Kausar, Hina; Russell, Gilandra K.; Munagala, Radha; Ravoori, Srivani (2012-08-01). "Controlled-release systemic delivery - a new concept in cancer chemoprevention". Carcinogenesis. 33 (8): 1608–1615. doi:10.1093/carcin/bgs209. ISSN 1460-2180. PMC 3499062. PMID 22696595.
  19. ^ Samadi, Abbas K.; Mukerji, Ridhwi; Shah, Anuj; Timmermann, Barbara N.; Cohen, Mark S. (2010-12-01). "A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo". Surgery. 148 (6): 1228–1236, discussion 1236. doi:10.1016/j.surg.2010.09.026. ISSN 1532-7361. PMC 3088305. PMID 21134556.

Further reading

  1. Stan, Silvia D.; Zeng, Yan; Singh, Shivendra V. (2008-01-01). "Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells". Nutrition and Cancer. 60 Suppl 1: 51–60. doi:10.1080/01635580802381477.ISSN 1532-7914. PMC: 2597540. PMID 19003581.
  2. Lee, Wonhwa; Kim, Tae Hoon; Ku, Sae-Kwang; Min, Kyoung-Jin; Lee, Hyun-Shik; Kwon, Taeg Kyu; Bae, Jong-Sup (2012-07-01). "Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models".Toxicology and Applied Pharmacology 262 (1): 91–98.doi:10.1016/j.taap.2012.04.025. ISSN 1096-0333.PMID 22561332.
  3. Fong, Miranda Y.; Jin, Shunying; Rane, Madhavi; Singh, Raj K.; Gupta, Ramesh; Kakar, Sham S. (2012-01-01). "Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer". PloS One 7 (7): e42265.doi:10.1371/journal.pone.0042265. ISSN 1932-6203.PMC: 3408484. PMID 22860102.
  4. Khan, Saad; Rammeloo, Ashley W.; Heikkila, John J. (2012-01-01). "Withaferin A induces proteasome inhibition, endoplasmic reticulum stress, the heat shock response and acquisition of thermotolerance". PloS One 7(11): e50547. doi:10.1371/journal.pone.0050547.ISSN 1932-6203. PMC: 3511540. PMID 23226310.
  5. Chaurasiya, Narayan D.; Sangwan, Neelam S.; Sabir, Farzana; Misra, Laxminarain; Sangwan, Rajender S. (2012-10-01). "Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L. (Dunal)". Plant Cell Reports 31(10): 1889–1897. doi:10.1007/s00299-012-1302-4.ISSN 1432-203X. PMID 22733207.
  6. Ashkenazi, Shaked; Plotnikov, Alexander; Bahat, Anat; Ben-Zeev, Efrat; Warszawski, Shira; Dikstein, Rivka (2016-04-15). "A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug". Molecular and Cellular Biology 36 (8): 1237–1247.doi:10.1128/MCB.00895-15. ISSN 1098-5549.PMID 26830231
  7. Jayaprakasam, Bolleddula; Zhang, Yanjun; Seeram, Navindra P; Nair, Muraleedharan G (2003-11-21). "Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves". Life Sciences 74 (1): 125–132. doi:10.1016/j.lfs.2003.07.007.
  8. Yang, Huanjie; Shi, Guoqing; Dou, Q. Ping (2007-02-01). "The Tumor Proteasome Is a Primary Target for the Natural Anticancer Compound Withaferin A Isolated from “Indian Winter Cherry”". Molecular Pharmacology 71 (2): 426–437.doi:10.1124/mol.106.030015. ISSN 1521-0111.PMID 17093135.
  9. Malik, Fayaz; Kumar, Ajay; Bhushan, Shashi; Khan, Sheema; Bhatia, Aruna; Suri, Krishan Avtar; Qazi, Ghulam Nabi; Singh, Jaswant (2007-09-15). "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 12 (11): 2115–2133.
  10. Devi, P. U. (1996-10-01). "Withania somnifera Dunal (Ashwagandha): potential plant source of a promising drug for cancer chemotherapy and radiosensitization". Indian Journal of Experimental Biology34 (10): 927–932. ISSN 0019-5189. PMID 9055640
  11. Stan, Silvia D.; Hahm, Eun-Ryeong; Warin, Renaud; Singh, Shivendra V. (2008-09-15). "Withaferin A Causes FOXO3a- and Bim-Dependent Apoptosis and Inhibits Growth of Human Breast Cancer Cells In vivo".Cancer Research 68 (18): 7661–7669. doi:10.1158/0008-5472.CAN-08-1510. ISSN 0008-5472. PMC: 2562581.PMID 18794155.
  12. Kim, Ju-Hee; Kim, Song-Ja (2014-01-01)."Overexpression of microRNA-25 by withaferin A induces cyclooxygenase-2 expression in rabbit articular chondrocytes". Journal of Pharmacological Sciences 125(1): 83–90. ISSN 1347-8648. PMID 24748433.
  13. Lee, In-Chul; Choi, Bu Young (2016-01-01)."Withaferin-A-A Natural Anticancer Agent with Pleitropic Mechanisms of Action". International Journal of Molecular Sciences 17 (3). doi:10.3390/ijms17030290. ISSN 1422-0067. PMC: 4813154. PMID 26959007.
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