This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, W. Articles by Bertino, J. R. Search for Related Content PubMed PubMed Citation Articles by Li, W. Articles by Bertino, J. R.

Selective Sensitization of Retinoblastoma Protein-deficient Sarcoma Cells to Doxorubicin by Flavopiridol-mediated Inhibition of Cyclin-dependent Kinase 2 Kinase Activity¹

Laboratory of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

We examined the effects of flavopiridol (FP), a cyclin-dependent kinase inhibitor, on doxorubicin (DOX)-induced cell killing in an osteosarcoma cell line (SaOs-2) that lacks functional retinoblastoma protein (pRb). The IC₅₀ value for DOX was 7-fold lower when combined with a low dose (100 nM) FP in pRb-deficient SaOs-2 cells than in the absence of FP. In contrast, the IC₅₀ value for DOX was not decreased in the presence of 100 nM FP in pRb-restored SaOs-2 cells. Consistent with this, FP enhanced DOX-induced activation of caspase-3, which correlates with apoptosis, in pRb-deficient cells but not in pRb-restored cells. Additional studies showed that FP decreased DOX-induced cell accumulation in S phase in retinoblastoma-restored cells but not in pRb-deficient cells. An increased expression of p21 and inhibition of cyclin-dependent kinase 2 kinase activity by FP was also observed in pRb-deficient cells but not in retinoblastoma-restored SaOs-2 cells. We conclude that pRb plays a key role in determining whether FP selectively sensitizes DOX-induced cell killing in human sarcoma cells. Because lack of functional pRb is a common abnormality in human cancers, the combination of FP with DOX in tumors lacking pRb would be worthy of further investigation.

This article has been cited by other articles:

				T. Budak-Alpdogan, B. Chen, A. Warrier, D. J. Medina, D. Moore, and J. R. Bertino Retinoblastoma Tumor Suppressor Gene Expression Determines the Response to Sequential Flavopiridol and Doxorubicin Treatment in Small-Cell Lung Carcinoma Clin. Cancer Res., February 15, 2009; 15(4): 1232 - 1240. [Abstract] [Full Text] [PDF]

				A. J. Russo, P. G. Magro, Z. Hu, W.-W. Li, R. Peters, J. Mandola, D. Banerjee, and J. R. Bertino E2F-1 Overexpression in U2OS Cells Increases Cyclin B1 Levels and cdc2 Kinase Activity and Sensitizes Cells to Antimitotic Agents. Cancer Res., July 15, 2006; 66(14): 7253 - 7260. [Abstract] [Full Text] [PDF]

				G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF]

				K. C. Bible, J. L. Lensing, S. A. Nelson, Y. K. Lee, J. M. Reid, M. M. Ames, C. R. Isham, J. Piens, S. L. Rubin, J. Rubin, et al. Phase 1 Trial of Flavopiridol Combined with Cisplatin or Carboplatin in Patients with Advanced Malignancies with the Assessment of Pharmacokinetic and Pharmacodynamic End Points Clin. Cancer Res., August 15, 2005; 11(16): 5935 - 5941. [Abstract] [Full Text] [PDF]

				J. I. Geller, K. Szekely-Szucs, I. Petak, B. Doyle, and J. A. Houghton P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells Cancer Res., September 1, 2004; 64(17): 6296 - 6303. [Abstract] [Full Text] [PDF]

				B. Rau, I. Sturm, H. Lage, S. Berger, U. Schneider, S. Hauptmann, P. Wust, H. Riess, P. M. Schlag, B. Dorken, et al. Dynamic Expression Profile of p21WAF1/CIP1 and Ki-67 Predicts Survival in Rectal Carcinoma Treated With Preoperative Radiochemotherapy J. Clin. Oncol., September 15, 2003; 21(18): 3391 - 3401. [Abstract] [Full Text] [PDF]

				D.-M. Kim, S.-Y. Koo, K. Jeon, M. H. Kim, J. Lee, C. Y. Hong, and S. Jeong Rapid Induction of Apoptosis by Combination of Flavopiridol and Tumor Necrosis Factor (TNF)-{alpha} or TNF-related Apoptosis-inducing Ligand in Human Cancer Cell Lines Cancer Res., February 1, 2003; 63(3): 621 - 626. [Abstract] [Full Text] [PDF]

				N. R. Wall, D. S. O'Connor, J. Plescia, Y. Pommier, and D. C. Altieri Suppression of Survivin Phosphorylation on Thr34 by Flavopiridol Enhances Tumor Cell Apoptosis Cancer Res., January 1, 2003; 63(1): 230 - 235. [Abstract] [Full Text] [PDF]

				T. Sandal, C. Stapnes, H. Kleivdal, L. Hedin, and S. O. Doskeland A Novel, Extraneuronal Role for Cyclin-dependent Protein Kinase 5 (CDK5). MODULATION OF cAMP-INDUCED APOPTOSIS IN RAT LEUKEMIA CELLS J. Biol. Chem., May 31, 2002; 277(23): 20783 - 20793. [Abstract] [Full Text] [PDF]

				C. B. Matranga and G. I. Shapiro Selective Sensitization of Transformed Cells to Flavopiridol-induced Apoptosis following Recruitment to S-Phase Cancer Res., March 1, 2002; 62(6): 1707 - 1717. [Abstract] [Full Text] [PDF]