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Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH 727965 and a heat shock protein 90 inhibitor

fu, wei and chu, baoky and pledger, w.jack (2013) Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH 727965 and a heat shock protein 90 inhibitor. Cell Death and Disease, 4 (3). ISSN 2041-4889

Abstract

Purpose. Osteosarcoma (OS) is an aggressive bone cancer typically observed in adolescents and young adults. Metastatic relapse after standard chemotherapy and surgical excision accounts primarily for treatment failure. New treatment options are needed, and toward this goal, we examined the effects of a novel drug combination on the survival of OS cells.
Experimental Design. Drugs were tested on OS cultures prepared from resected tumors that did or did not respond to neoadjuvant chemotherapy. Drugs tested included NVP-AUY922 (AUY) and three additional heat shock protein 90 (Hsp90) inhibitors, and the cyclin-dependent kinase inhibitor SCH 727965 (SCH). As indicators of apoptosis, phosphatidylserine externalization, caspase activation, and Bax localization were monitored.
Results. All OS cultures apoptosed when co-treated with SCH and an Hsp90 inhibitor; Hsp90 inhibitors were not apoptotic as single agents, whereas SCH was weakly apoptotic. Bax accumulated in the mitochondria of co-treated cells but was primarily cytosolic in cells receiving either agent alone. SCH and AUY induced apoptosis when applied to cells simultaneously or when AUY was added to and removed from cells before addition of SCH. Sequential treatment was most effective when cells received AUY for ~12 hr and when SCH was presented to cells immediately after AUY removal. SCH and AUY cooperatively induced the apoptosis of other sarcoma types but did not affect the survival of normal osteoblasts.
Conclusion. SCH plus AUY represents a promising drug combination for treatment of OS and perhaps other sarcomas. We suggest it induces apoptosis at least in part by eliciting events upstream of Bax translocation.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/7902

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