The Mechanism of Action of Unique Small Molecules that Inhibit the Pim Protein Kinase Blocking Prostate Cancer Cell Growth
Revised final rept. 1 May 2009-30 Apr 2012
MEDICAL UNIV OF SOUTH CAROLINA CHARLESTON
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The Pim protein kinase is over expressed in prostate cancer. To clarify the role of this protein in regulating prostate cancer growth we have investigated its mechanism of action. We have examined the ability of small molecule inhibitors of this kinase to combine with other agents and have developed two rationally developed dual therapies. First, because overexpression of Bcl-2 family members is implicated in chemotherapeutic resistance in prostate cancer, we investigated the cooperative effects of Pim kinase inhibition with ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Second, we demonstrate that inhibition of AKT in prostate cancer cell lines not only induces the expression of multiple RTKs, but increases the protein levels of serine threonine protein kinase Pim-1. Pim-1 activity is identified as essential in the feedback regulation of RTK levels by AKT inhibition. Both tissue culture and animal experiments demonstrate that the combination of AKT and Pim inhibitors provides synergistic inhibition of tumor growth. Thus Pim inhibitor has potential activity to treat this cancer.
- Medicine and Medical Research