Withaferin A inhibits osteosarcoma cells through inactivation of Notch-1 signalling
Human osteosarcoma cells were treated with withaferin A and the antiproliferative activity was evaluated by the 3-(4, 5 dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Real-time RT-PCR and western blot were used to investigate whether the down-regulation of Notch-1 contributes to withaferin A-induced inhibition of proliferation in osteosar-coma cells. The results showed that withaferin A caused marked inhibition of osteosarcoma cell growth and G2?M phase cell cycle arrest. This was associated with concomitant attenuation of Notch-1 and down-regulation of its downstream genes, such as matrix metalloproteinases. These results suggest that antitumor activity of withaferin A is mediated through a novel mechanism involving inactivation of the Notch-1 signalling pathway. Our data provide the first evidence that the down regulation of Notch-1 by withaferin A may be an effective approach for the treatment of osteosarcoma.
Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 1999; 341: 342-52.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002; 20: 776-90.
Engin F, Bertin T, Ma O, Jiang MM, Wang L, Sutton RE, et al. Notch signalling contributes to the pathogenesis of human osteosarcomas. Hum Mol Genet. 2009; 18: 1464-70.
Hughes DP. How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treat Res. 2009; 152: 479-96.
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-kappaB (NF-jB) activation and NF-jB-regulated gene expression. Mol Cancer Ther. 2006; 5: 1434-45.
Jang MS, Miao H, Carlesso N, Shelly L, Zlobin A, Darack N et al.Notch-1 regulates cell death independently of differentiation in murine erythroleukemia cells through multiple apoptosis and cell cycle pathways. J Cell Physiol. 2004; 199: 418-33.
Jayaprakasam B, Nair MG. Cyclooxygenase-2 enzyme inhibitory withanolides from Withania somnifera leaves. Tetrahedron 2003; 59: 841-49.
Kaileh M, Vanden Berghe W, Heyerick A, Horion J, Piette J, Libert C, et al. Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J Biol Chem. 2007; 282: 4253-64.
Katoh M. Notch signaling in gastrointestinal tract (review). Int J Oncol 2007; 30: 247-51
Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006; 107: 2223-33.
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: 202-10.
Li JL, Harris AL. Notch signaling from tumor cells: A new mechanism of angiogenesis. Cancer Cell 2005; 8: 1-3.
Petrilli AS, de Camargo B, Filho VO, Bruniera P, Brunetto AL, Jesus-Garcia R, et al. Results of the Brazilian osteosarcoma treatment group studies III and IV: Prognostic factors and
impact on survival. J Clin Oncol. 2006; 24: 1161-68
Ramdass B, Maliekal TT, Lakshmi S, Rehman M, Rema P, Nair P, et al. Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression. Gynecol Oncol. 2007; 104: 352-61.
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: 246-53.
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: 7661-69.
Subbaraju GV, Vanisree M, Rao CV, Sivaramakrishna C, Sridhar P, Jayaprakasam B, et al. Ashwagandhanolide, a bioactive dimeric thiowithanolide isolated from the roots of Withania somnifera. J Nat Prod. 2006; 69: 1790-92.
Tanaka M, Setoguchi T, Hirotsu M, Gao H, Sasaki H, Matsunoshita Y, et al. Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer 2009; 100: 1957-65.
Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther. 2006; 5: 483-93.
Zhang P, Yang Y, Zweidler-McKay PA, Hughes DP. Critical role of Notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res. 2008; 14: 2962-69.
Copyright (c) 2014 Yang Chen, Xiang-Zhen Han, Wei Wang, Ren-Tao Zhao, Xiao Li
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