The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Withaferin A targets heat shock protein 90 in pancreatic cancer cells
Open accessAbstract
The purpose of this study is to investigate the efficacy and the mechanism of Hsp90 inhibition of Withaferin A (WA), a steroidal lactone occurring in Withania somnifera, in pancreatic cancer in vitro and in vivo. Withaferin A exhibited potent antiproliferative activity against pancreatic cancer cells in vitro (with IC50s of 1.24, 2.93 and 2.78 μM) in pancreatic cancer cell lines Panc-1, MiaPaca2 and BxPc3, respectively. Annexin V staining showed that WA induced significant apoptosis in Panc-1 cells in a dose dependent manner. Western blotting demonstrated that WA inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins (Akt, Cdk4 and glucocorticoid receptor), which was reversed by the proteasomal inhibitor, MG132. WA-Biotin pull-down assay of Hsp90 using Panc-1 cancer cell lysates and purified Hsp90 showed that WA-biotin binds to C-terminus of Hsp90, which was competitively blocked by unlabeled WA. Co-immunoprecipitation exhibited that WA (10 μM) disrupted Hsp90-Cdc37 complexes from 1–24 hour post treatment, while it neither blocked ATP binding to Hsp90, nor changed Hsp90-P23 association. WA (3, 6 mg/kg) inhibited tumor growth in pancreatic Panc-1 xenografts by 30% and 58%, respectively. These data demonstrate that Withaferin A binds Hsp90, inhibits Hsp90 chaperone activity through an ATP independent mechanism, results in Hsp90 client protein degradation, and exhibits in vivo anticancer activity against pancreatic cancer.
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Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., & Thun, M. J. (2007) · CA: A Cancer Journal for Clinicians · doi:10.3322/canjclin.57.1.43 · Cited by 7,439
Natural products as sources of new drugs over the period 1981–2002
Newman, D. J., Cragg, G. M., & Snader, K. M. (2003) · Journal of Natural Products · doi:10.1021/np030096l · Cited by 3,082
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502
Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle
Siligardi, G., Hu, B., Panaretou, B., Piper, P. W., Pearl, L. H., & Prodromou, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410562200 · Cited by 207 · cited 1×
“Furthermore, P23 and Cdc37 were demonstrated to bind to the same sites on the N-terminus of Hsp90, and binding of P23 and Cdc37 to Hsp90 is mutually exclusive [35,58].”
Cited by
Heat Shock Proteins and Cancer
Wu, J., Liu, T., Rios, Z., Mei, Q., Lin, X., & Cao, S. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.11.009 · Cited by 696
Structure, Function, and Regulation of the Hsp90 Machinery
Biebl, M. M., & Buchner, J. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a034017 · Cited by 304
Paul, S., Chakraborty, S., Anand, U., Dey, S., Nandy, S., Ghorai, M., Saha, S. C., Patil, M. T., Kandimalla, R., Proćków, J., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112175 · Cited by 306
Thaiparambil, J. T., Bender, L., Ganesh, T., Kline, E., Patel, P., Liu, Y., Tighiouart, M., Vertino, P. M., Harvey, R. D., Garcia, A., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.25938 · Cited by 289
Vimentin Diversity in Health and Disease
Danielsson, F., Peterson, M. K., Caldeira Araújo, H., Lautenschläger, F., & Gad, A. K. B. (2018) · Cells · doi:10.3390/cells7100147 · Cited by 265
Metadata
- Authors
- Yu, Y., Hamza, A., Zhang, T., Gu, M., Zou, P., Newman, B., Li, Y., Gunatilaka, A. A. L., Zhan, C.-G., & Sun, D.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 79
- Issue
- 4
- Pages
- 542-551
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2049763771
- Cited by
- 316
- References
- 4
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- green
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- Yu, Y., Hamza, A., Zhang, T., Gu, M., Zou, P., Newman, B., Li, Y., Gunatilaka, A. A. L., Zhan, C.-G., & Sun, D. (2010). Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochemical Pharmacology. https://doi.org/10.1016/j.bcp.2009.09.017
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