Phospholipase A2 as therapeutic targets in prostate cancer
Mock, Jason Nicholas
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The ultimate goal of this work is to improve chemotherapy through molecular targeting. Cancer cells undergo a myriad of pathological changes before a solid tumor forms. This is evidenced by dramatic over expression of oncogenes or other enzymes. One such enzyme family is phospholipase A2 (PLA2), which are esterases that cleave phospholipids at the sn-2 position to yield a lysophospholipid and a fatty acid. There are six subfamilies of PLA2, including calcium-independent PLA2 (iPLA2) and secretory PLA2 (sPLA2). These two subfamilies will be the primary focus of this research. Each of these classes has distinct pathophysiological roles and can be exploited differently. iPLA2 are involved in membrane phospholipid homeostasis and signal transduction pathways related to proliferation and migration. Therefore, inhibition of iPLA2 may halt or slow cancer growth. To test this hypothesis, putative iPLA2 inhibitors were synthesized and screened for their ability to slow proliferation, inhibit iPLA2, and alter the cell cycle in a prostate cancer model. sPLA2 are commonly over expressed in prostate tumors as well as other cancers, and appear to have oncogenic properties. We developed liposomes that interact with sPLA2, and show that release from these sPLA2 responsive liposomes (SPRL) can be mediated by sPLA2. In vitro evaluation of SPRL, which was performed in several prostate cancer cell lines, showed that these formulations produce levels of cytotoxicity similar to free drug, and uptake of drug and carrier are cell- and carrier-dependent. Cytotoxicity was not different between formulations, nor was cytotoxicity or uptake affected by inhibition of sPLA2. This suggests that multiple mechanisms are mediating the observed cytotoxicity. Differential expression of sPLA2 isoforms as well as the PLA2 Receptor (PLA2R) may be also mediating formulation disposition. Preliminary in vivo studies suggest that SPRL are more effective at slowing tumor growth compared to conventional liposome formulations. In conclusion, this work demonstrates that both iPLA2 and sPLA2 can be utilized as targets for molecular based therapeutics for prostate cancer. This targeting strategy may hold tremendous potential not only for the treatment of prostate cancer, but also for other pathologies where PLA2 are over expressed.