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-kappaB 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.