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Withaferin-A as a Potential Candidate for Cancer Therapy: Experimental Evidence of Its Effects on Telomerase Plus and Minus Cancer Cells

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Science of Ashwagandha: Preventive and Therapeutic Potentials
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Abstract

Telomeres (specialized ends of eukaryotic chromosomes) shorten with each round of division in normal human cells. In contrast, cancer cells maintain their telomere length and have been defined as their most consistent attribute. It is achieved by activation of telomere maintenance mechanisms that may either involve up regulation of a specialized reverse transcriptase, telomerase (Telomerase positive, TEP) or recombination based Alternative Lengthening of Telomeres (ALT). Telomere shortening is considered as a tumor suppressor mechanism and hence the drugs to activate this mechanism are deemed anticancer agents. In this chapter we describe the basic mechanisms of telomere length maintenance and their targeting in anticancer therapy. Use of Withaferin-A as a potential anticancer drug for TEP and ALT cells is discussed. Whereas ALT cells escape the deleterious effect of telomerase inhibitors in cancer therapy, Withaferin-A kills both TEP and ALT cells effectively. Thus, Withaferin-A emerges as a promising potential candidate for cancer therapy.

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References

  • Bargagna-Mohan P, Deokule SP, Thompson K, Wizeman J, Srinivasan C, Vooturi S, Kompella UB, Mohan R (2013) Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis. PLoS One 8:e63881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blackburn EH (1991) Structure and function of telomeres. Nature 350:569–573

    Article  CAS  PubMed  Google Scholar 

  • Blackburn EH (2001) Switching and signaling at the telomere. Cell 106:661–673

    Article  CAS  PubMed  Google Scholar 

  • Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352

    Article  CAS  PubMed  Google Scholar 

  • Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR (1995) Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14:4240–4248

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR (1997a) Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 3:1271–1274

    Article  CAS  PubMed  Google Scholar 

  • Bryan TM, Marusic L, Bacchetti S, Namba M, Reddel RR (1997b) The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. Hum Mol Genet 6:921–926

    Article  CAS  PubMed  Google Scholar 

  • Cao Y, Huschtscha LI, Nouwens AS, Pickett HA, Neumann AA, Chang AC, Toouli CD, Bryan TM, Reddel RR (2008) Amplification of telomerase reverse transcriptase gene in human mammary epithelial cells with limiting telomerase RNA expression levels. Cancer Res 68:3115–3123

    Article  CAS  PubMed  Google Scholar 

  • Cesare AJ, Reddel RR (2010) Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet 11:319–330

    Article  CAS  PubMed  Google Scholar 

  • Chi F, Jong TD, Wang L, Ouyang Y, Wu C, Li W, Huang SH (2010) Vimentin-mediated signalling is required for IbeA+ E. coli K1 invasion of human brain microvascular endothelial cells. Biochem J 427:79–90

    Article  CAS  PubMed  Google Scholar 

  • Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR (2007) Protein composition of catalytically active human telomerase from immortal cells. Science 315:1850–1853

    Article  CAS  PubMed  Google Scholar 

  • Colgin L, Reddel R (2004) Telomere biology: a new player in the end zone. Curr Biol 14:R901–R902

    Article  CAS  PubMed  Google Scholar 

  • Cong Y, Shay JW (2008) Actions of human telomerase beyond telomeres. Cell Res 18:725–732

    Article  CAS  PubMed  Google Scholar 

  • Cong YS, Wright WE, Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev 66:407–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conomos D, Pickett HA, Reddel RR (2013) Alternative lengthening of telomeres: remodeling the telomere architecture. Front Oncol 3:27

    Article  PubMed  PubMed Central  Google Scholar 

  • Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, Sedivy JM, Weinberg RA (1998) Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci U S A 95:14723–14728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cristofari G, Sikora K, Lingner J (2007) Telomerase unplugged. ACS Chem Biol 2:155–158

    Article  CAS  PubMed  Google Scholar 

  • Cui ZG, Piao JL, Rehman MU, Ogawa R, Li P, Zhao QL, Kondo T, Inadera H (2014) Molecular mechanisms of hyperthermia-induced apoptosis enhanced by withaferin A. Eur J Pharmacol 723:99–107

    Article  CAS  PubMed  Google Scholar 

  • d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198

    Article  PubMed  Google Scholar 

  • de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110

    Article  PubMed  Google Scholar 

  • Dunham MA, Neumann AA, Fasching CL, Reddel RR (2000) Telomere maintenance by recombination in human cells. Nat Genet 26:447–450

    Article  CAS  PubMed  Google Scholar 

  • Gao R, Shah N, Lee JS, Katiyar SP, Li L, Oh E, Sundar D, Yun CO, Wadhwa R, Kaul SC (2014) Withanone-rich combination of Ashwagandha withanolides restricts metastasis and angiogenesis through hnRNP-K. Mol Cancer Ther 13:2930–2940

    Article  CAS  PubMed  Google Scholar 

  • Giardini MA, Segatto M, da Silva MS, Nunes VS, Cano MI (2014) Telomere and telomerase biology. Prog Mol Biol Transl Sci 125:1–40

    Article  CAS  PubMed  Google Scholar 

  • Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460

    Article  CAS  PubMed  Google Scholar 

  • Hartwig FP, Collares T (2013) Telomere dysfunction and tumor suppression responses in dyskeratosis congenita: balancing cancer and tissue renewal impairment. Ageing Res Rev 12:642–652

    Article  CAS  PubMed  Google Scholar 

  • Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC (1990) Telomere reduction in human colorectal carcinoma and with ageing. Nature 346:866–868

    Article  CAS  PubMed  Google Scholar 

  • Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I (1998) X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 19:32–38

    Article  CAS  PubMed  Google Scholar 

  • Henson JD, Reddel RR (2010) Assaying and investigating Alternative Lengthening of Telomeres activity in human cells and cancers. FEBS Lett 584:3800–3811

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, Ding Z, Ying H, Boutin AT, Zhang H, Johnson S, Ivanova E, Kost-Alimova M, Protopopov A, Wang YA, Shirihai OS, Chin L, DePinho RA (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148:651–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T (1999) p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283:1321–1325

    Article  CAS  PubMed  Google Scholar 

  • Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA, Reddel RR (2012) Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep 13:52–59

    Article  CAS  Google Scholar 

  • Lee J, Hahm ER, Marcus AI, Singh SV (2015) Withaferin A inhibits experimental epithelial-mesenchymal transition in MCF-10A cells and suppresses vimentin protein level in vivo in breast tumors. Mol Carcinog 54:417–429

    Article  CAS  PubMed  Google Scholar 

  • Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB (1992) Telomere end-replication problem and cell aging. J Mol Biol 225:951–960

    Article  CAS  PubMed  Google Scholar 

  • Londono-Vallejo JA (2008) Telomere instability and cancer. Biochimie 90:73–82

    Article  CAS  PubMed  Google Scholar 

  • Lv TZ, Wang GS (2015) Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins. Exp Ther Med 10:323–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maciel-Baron LA, Morales-Rosales SL, Aquino-Cruz AA, Triana-Martinez F, Galvan-Arzate S, Luna-Lopez A, Gonzalez-Puertos VY, Lopez-Diazguerrero NE, Torres C, Konigsberg M (2016) Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli. Age (Dordr) 38:26

    Article  CAS  Google Scholar 

  • Martinez P, Blasco MA (2010) Role of shelterin in cancer and aging. Aging Cell 9:653–666

    Article  CAS  PubMed  Google Scholar 

  • Martinez P, Blasco MA (2011) Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer 11:161–176

    Article  CAS  PubMed  Google Scholar 

  • McDonald KL, McDonnell J, Muntoni A, Henson JD, Hegi ME, von Deimling A, Wheeler HR, Cook RJ, Biggs MT, Little NS, Robinson BG, Reddel RR, Royds JA (2010) Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival. J Neuropathol Exp Neurol 69:729–736

    Article  PubMed  Google Scholar 

  • Mender I, Shay JW (2015) Telomere Dysfunction Induced Foci (TIF) Analysis. Bio Protoc 5:pii: e1656

    Google Scholar 

  • Mengual Gomez DL, Armando RG, Farina HG, Gomez DE (2014) Telomerase and telomere: their structure and dynamics in health and disease. Medicina (B Aires) 74:69–76

    Google Scholar 

  • Munagala R, Kausar H, Munjal C, Gupta RC (2011) Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis 32:1697–1705

    Article  CAS  PubMed  Google Scholar 

  • Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201:1496–1499

    CAS  PubMed  Google Scholar 

  • Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334

    Article  CAS  PubMed  Google Scholar 

  • Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch-Machin MA, Kirkwood TB, von Zglinicki T (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5:e110

    Article  PubMed  PubMed Central  Google Scholar 

  • Patel TN, Vasan R, Gupta D, Patel J, Trivedi M (2015) Shelterin proteins and cancer. Asian Pac J Cancer Prev 16:3085–3090

    Article  PubMed  Google Scholar 

  • Petroni M, Sardina F, Heil C, Sahun-Roncero M, Colicchia V, Veschi V, Albini S, Fruci D, Ricci B, Soriani A, Di Marcotullio L, Screpanti I, Gulino A, Giannini G (2015) The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress. Cell Death Differ 23:197–206

    Article  PubMed  PubMed Central  Google Scholar 

  • Schmitt E, Paquet C, Beauchemin M, Bertrand R (2007) DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis. J Zhejiang Univ Sci B 8:377–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shay JW (1997) Telomerase in human development and cancer. J Cell Physiol 173:266–270

    Article  CAS  PubMed  Google Scholar 

  • Shay JW, Reddel RR, Wright WE (2012) Cancer and telomeres-an ALTernative to telomerase. Science 336:1388–1390

    Article  CAS  PubMed  Google Scholar 

  • Sikora E, Bielak-Zmijewska A, Mosieniak G (2014) Cellular senescence in ageing, age-related disease and longevity. Curr Vasc Pharmacol 12:698–706

    Article  CAS  PubMed  Google Scholar 

  • Singhapol C, Pal D, Czapiewski R, Porika M, Nelson G, Saretzki GC (2013) Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PLoS One 8:e52989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suman S, Das TP, Sirimulla S, Alatassi H, Ankem MK, Damodaran C (2016) Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells. Oncotarget 7:13854–13864

    Article  PubMed  PubMed Central  Google Scholar 

  • Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Curr Biol 13:1549–1556

    Article  CAS  PubMed  Google Scholar 

  • Thaiparambil JT, Bender L, Ganesh T, Kline E, Patel P, Liu Y, Tighiouart M, Vertino PM, Harvey RD, Garcia A, Marcus AI (2011) Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer 129:2744–2755

    Article  CAS  PubMed  Google Scholar 

  • Um HJ, Min KJ, Kim DE, Kwon TK (2012) Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun 427:24–29

    Article  CAS  PubMed  Google Scholar 

  • van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413

    Article  PubMed  Google Scholar 

  • von Figura G, Hartmann D, Song Z, Rudolph KL (2009) Role of telomere dysfunction in aging and its detection by biomarkers. J Mol Med (Berl) 87:1165–1171

    Article  Google Scholar 

  • Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, Dokal I (2008) Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 105:8073–8078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wadhwa R, Kaul Z, Kaul SC (2016) Cell cycle checkpoints and senescence. In: Suresh ISR, Hayflick L (eds) Cellular ageing and replicative senescence. Springer, Cham, pp 145–166

    Google Scholar 

  • Watson JD (1972) Origin of concatemeric T7 DNA. Nat New Biol 239:197–201

    Article  CAS  PubMed  Google Scholar 

  • White LK, Wright WE, Shay JW (2001) Telomerase inhibitors. Trends Biotechnol 19:114–120

    Article  CAS  PubMed  Google Scholar 

  • Widodo N, Kaur K, Shrestha BG, Takagi Y, Ishii T, Wadhwa R, Kaul SC (2007) 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 13:2298–2306

    Article  CAS  PubMed  Google Scholar 

  • Widodo N, Takagi Y, Shrestha BG, Ishii T, Kaul SC, Wadhwa R (2008) Selective killing of cancer cells by leaf extract of Ashwagandha: components, activity and pathway analyses. Cancer Lett 262:37–47

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR (1999) Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res 59:4175–4179

    CAS  PubMed  Google Scholar 

  • von Zglinicki T, Burkle A, Kirkwood TB (2001) Stress, DNA damage and ageing - an integrative approach. Exp Gerontol 36:1049–1062

    Article  Google Scholar 

  • Yu Y, Katiyar SP, Sundar D, Kaul Z, Miyako E, Zhang Z, Kaul SC, Reddel RR, Wadhwa R (2017) Withaferin-A kills cancer cells with and without telomerase: chemical, computational and experimental evidences. Cell Death Dis 8:e2755

    Google Scholar 

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Correspondence to Renu Wadhwa .

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Kaul, Z., Yu, Y., Kaul, S.C., Wadhwa, R. (2017). Withaferin-A as a Potential Candidate for Cancer Therapy: Experimental Evidence of Its Effects on Telomerase Plus and Minus Cancer Cells. In: Kaul, S., Wadhwa, R. (eds) Science of Ashwagandha: Preventive and Therapeutic Potentials. Springer, Cham. https://doi.org/10.1007/978-3-319-59192-6_9

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