Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor
Open Access
- 28 March 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 4 (3), e566
- https://doi.org/10.1038/cddis.2013.101
Abstract
Osteosarcoma (OS) is an aggressive bone cancer typically observed in adolescents and young adults. Metastatic relapse accounts primarily for treatment failure, and obstacles to improving cure rates include a lack of efficacious agents. Our studies show apoptosis of OS cells prepared from localized and metastatic tumors by a novel drug combination: SCH727965 (SCH), a cyclin-dependent kinase inhibitor, and NVP-AUY922 (AUY) or other heat shock protein 90 inhibitor. SCH and AUY induced apoptosis when added simultaneously to cells and when AUY was added to and removed from cells before SCH addition. Sequential treatment was most effective when cells received AUY for ∼12 h and when SCH was presented to cells immediately after AUY removal. The apoptotic protein Bax accumulated in mitochondria of cotreated cells but was primarily cytosolic in cells receiving either agent alone. Additional data show that SCH and AUY cooperatively induce the apoptosis of other sarcoma cell types but not of normal osteoblasts or fibroblasts, and that SCH and AUY individually inhibit cell cycle progression throughout the cell cycle. We suggest that the combination of SCH and AUY may be an effective new strategy for treatment of OS.Keywords
This publication has 53 references indexed in Scilit:
- Multidrug Resistance–Linked Gene Signature Predicts Overall Survival of Patients with Primary Ovarian Serous CarcinomaClinical Cancer Research, 2012
- A Meta-Analysis of Osteosarcoma Outcomes in the Modern Medical EraSarcoma, 2012
- Cytosolic BaxOnline Journal of Public Health Informatics, 2012
- Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative ActivityJournal of Medicinal Chemistry, 2011
- High-Content, High-Throughput Analysis of Cell Cycle Perturbations Induced by the HSP90 Inhibitor XL888PLOS ONE, 2011
- MDM2 Acts Downstream of p53 as an E3 Ligase to Promote FOXO Ubiquitination and DegradationOnline Journal of Public Health Informatics, 2009
- Principles of Cancer Therapy: Oncogene and Non-oncogene AddictionCell, 2009
- A stress protein interface of innate immunityEMBO Reports, 2008
- Inhibition of Hsp90 Leads to Cell Cycle Arrest and Apoptosis in Human Malignant Pleural MesotheliomaJournal of Thoracic Oncology, 2008
- The Bcl-2 apoptotic switch in cancer development and therapyOncogene, 2007