Withaferin A inhibits osteosarcoma cells through inactivation of Notch-1 signalling

  • Yang Chen Department of Bone Tumor, Linyi People’s Hospital, Shandong 276 003
  • Xiang-Zhen Han Department of Bone Tumor, Linyi People’s Hospital, Shandong 276 003
  • Wei Wang Department of Bone Tumor, Linyi People’s Hospital, Shandong 276 003
  • Ren-Tao Zhao Department of Bone Tumor, Linyi People’s Hospital, Shandong 276 003
  • Xiao Li Department of Bone Tumor, Linyi People’s Hospital, Shandong 276 003
Keywords: Withaferin A, Withanolides, Adenocarcinoma, Phosphorylation, Apoptosis

Abstract

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.

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Author Biography

Xiao Li, Department of Bone Tumor, Linyi People’s Hospital, Shandong 276 003
Emergency Department of Bone Tumor

References

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.

Published
2014-08-19
How to Cite
Chen, Y., X.-Z. Han, W. Wang, R.-T. Zhao, and X. Li. “Withaferin A Inhibits Osteosarcoma Cells through Inactivation of Notch-1 Signalling”. Bangladesh Journal of Pharmacology, Vol. 9, no. 3, Aug. 2014, pp. 364-70, doi:10.3329/bjp.v9i3.19568.
Section
Research Articles