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In vitro and In vivo Molecular Evidence for Better Therapeutic Efficacy of ABT-627 and Taxotere Combination in Prostate Cancer

¹ Department of Pathology, Barbara Ann Karmanos Cancer Institute; ² Department of Urology, Wayne State University, School of Medicine, Detroit, Michigan; and ³ Departments of Medicine and Urology, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Fazlul H. Sarkar, Department of Pathology, Karmanos Cancer Institute, Room 740 HWCRC Building, 4160 John R Street, Detroit, MI 48201. Phone: 313-576-8327; Fax: 313-576-8389; E-mail: fsarkar{at}med.wayne.edu.

Bone is the key metastatic site for prostate cancer. Endothelin 1 (ET-1) produced abundantly by prostate cancer cells binds to its receptor present on bone marrow stromal cells and favors osteoblastic response during bone metastases of prostate cancer. This suggests that interrupting ET-1 interaction with its endothelin A (ET_A) receptor could be useful for inhibiting prostate cancer bone metastasis and, as such, may enhance the therapeutic activity of docetaxel (Taxotere), the most commonly used drug for the treatment of metastatic prostate cancer. Therefore, the goal of our study was to obtain preclinical data supporting our hypothesis that the combined use of ET_A receptor antagonist (ABT-627; Atrasentan) with Taxotere will be superior in inducing apoptosis in vitro and inhibiting tumor growth in vivo in a SCID-hu model of experimental bone metastasis induced by C4-2b prostate cancer cells. In vitro studies were done on a panel of prostate cancer cell lines to understand the molecular basis of combination therapy, and we found that the combination was more effective in the inhibition of cell viability and induction of apoptosis in LNCaP and C4-2b cells (androgen receptor positive) but not in PC-3 cells. These results were correlated with inactivation of Akt/nuclear factor-B and its target genes. For in vivo studies, the therapeutic regimen was initiated when the tumor began showing signs of growth and treatment was continued for 5 weeks. Tumor volume and serum prostate-specific antigen were used as terminal index to evaluate the therapeutic advantage of combination therapy relative to a single regimen and untreated control. At termination, we found a 90% reduction in tumor volume by combination treatment relative to the untreated control group. Most importantly, the antitumor activity was associated with the down-regulation of molecular markers in tumor tissues that were similar to those observed in vitro. [Cancer Res 2007;67(8):3818–25]

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