Inhibition Of Prostate Cancer Skeletal Metastases By Targeting Cathepsin K
Abstract
We have previously shown that CatK is expressed not only by osteoclasts but also by prostate cancer (PCa) cells and stromal cells. Zledronic 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 (n=10/group):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. Therefore, 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2010
- Accession Number
- ADA535353
Entities
People
- Jian Zhang
Organizations
- University of Michigan