This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Hershberger, P. A. Articles by Johnson, C. S. Search for Related Content PubMed PubMed Citation Articles by Hershberger, P. A. Articles by Johnson, C. S.

Departments of Pharmacology [P. A. H., T. F. M., W-D. Y., E. G. Z., M. J. E., C. S. J.], Medicine [M. J. E., D. L. T., C. S. J.], Urology [D. L. T.], and The University of Pittsburgh Cancer Institute [M. J. E., D. L. T., C. S. J.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and Department of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands [J. H. M. S.]

1,25-Dihydroxyvitamin D₃ (1,25D₃) exhibits potent antitumor activity in the murine squamous cell carcinoma (SCC) SCCVII/SF, and the combination of 1,25D₃ with cisplatin (1,25D₃/cisplatin) demonstrates even greater activity. Because these agents possess different mechanisms of cytotoxicity, studies were initiated to define the mechanism by which the combination displays enhanced activity. Median dose-effect analysis demonstrates that 1,25D₃ and cisplatin act synergistically to inhibit SCC growth. When SCC cells were treated with 1,25D₃ (10 nM) and/or cisplatin (0.5 µg/ml), greater caspase-3 activation was observed for the combination than for either agent alone. This suggests that the enhanced cytotoxicity is, at least in part, due to greater induction of apoptosis. No alterations in cellular platinum concentration or platinum-DNA adducts were observed for 1,25D₃/cisplatin cotreatment compared with cisplatin treatment alone. Effects of the combination on cisplatin and 1,25D₃ signaling pathways in adherent (nonapoptotic) and floating (apoptotic) cells were explored. Cisplatin induced p53 and its downstream targets, p21^Cip1 (p21) and Bax, in both cell populations. In contrast, 1,25D₃ reduced p53, p21, and Bax to nearly undetectable levels in adherent cells. In the floating cells, 1,25D₃ reduced levels of p53 and p21, but Bax expression was maintained at control levels. Expression of these proteins in cells treated with 1,25D₃/cisplatin was similar to treatment with 1,25D₃ alone. The two agents also had divergent effects on survival and stress signaling pathways. Phospho-extracellular signal-regulated kinase 1/2 and phospho-Jun levels increased after treatment with cisplatin but decreased after treatment with 1,25D₃ and 1,25D₃/cisplatin. Moreover, cisplatin decreased levels of mitogen-activated protein kinase kinase kinase (MEKK-1), whereas 1,25D₃ up-regulated MEKK-1, and 1,25D₃/cisplatin further up-regulated MEKK-1. We propose that the increased cytotoxicity for 1,25D₃/cisplatin results from cisplatin enhancement of 1,25D₃-induced apoptotic signaling through MEKK-1.

This article has been cited by other articles:

				S. Attia, J. Eickhoff, G. Wilding, D. McNeel, J. Blank, H. Ahuja, A. Jumonville, M. Eastman, D. Shevrin, M. Glode, et al. Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer Clin. Cancer Res., April 15, 2008; 14(8): 2437 - 2443. [Abstract] [Full Text] [PDF]

				J. Tan, P. P. Dwivedi, P. Anderson, B. K. Nutchey, P. O'Loughlin, H. A. Morris, B. K. May, A. Ferrante, and C. S. Hii Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity Mol. Cancer Ther., December 1, 2007; 6(12): 3131 - 3138. [Abstract] [Full Text] [PDF]

				R. Kommagani, V. Payal, and M. P. Kadakia Differential Regulation of Vitamin D Receptor (VDR) by the p53 Family: p73-DEPENDENT INDUCTION OF VDR UPON DNA DAMAGE J. Biol. Chem., October 12, 2007; 282(41): 29847 - 29854. [Abstract] [Full Text] [PDF]