Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K
Annual rept. 15 Apr 2008-14 Apr 2009
PITTSBURGH UNIV PA
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We have previously shown that CatK is expressed not only by osteoclasts but also by prostate cancer PCa cells and stromal cells. Zoledronic acid ZA, a bisphosphonate which exerts beneficial effects in PCa patients with bone metastases, reduces both pain and skeletal related events. We hypothesized that combination of a bisphosphonate with the CatK inhibitor, through different inhibitory mechanisms, could diminish PCa progression in vivo. Accordingly, PCa C4-2B cells were inoculated into the tibiae of SCID mice. The mice were randomized into the following treatment groups n10group ZA, CatK inhibitor, the combination of ZA and CatK inhibitor, and saline vehicle alone. Test drugs were initiated at 4 weeks after the tumor cell inoculation and treatments were continued for 8 weeks. We found that CatK inhibitor significantly reduced skeletal tumor burden as determined by both tumor volume vs soft tissue volume ratio and serum PSA levels. In contrast, ZA less effectively diminished the skeletal tumor volume. ZA failed to decrease PSA levels. Importantly, combinations of the two agents were more effective in decreasing tumor volume than any single agent. Using one PCa cell line, we show for the first time that a CatK inhibitor diminishes PCa growth in bone and the inhibitory effects are enhanced in combination with ZA. More cell lines need to be tested.
- Medicine and Medical Research