642

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) promote tumor cell proliferation, survival, and invasion by binding to a family of G protein-coupled receptors collectively referred to as lysophospholipid (LPL) receptors. Therefore, novel agents that inhibit proteins in the LPL-stimulated signal transduction pathways hold promise as therapeutic agents for advanced prostate cancer. Our laboratory showed that 2-phenylthiazolidine-4-carboxylic acid amide (THZ) analogs of LPL demonstrate potent cytotoxicity against prostate cancer cells. LPA at concentrations of 0.01 to 10 μM induced cell growth up to 2-fold in androgen-insensitive PC-3, DU 145, PPC-1, and TSU-Pr1 prostate cancer cell lines, but not in androgen-sensitive LNCaP cells. Interestingly, LPA receptor-negative RH7777 cells also responded to prolonged exposure to LPA via an unknown mechanism. S1P was not effective promoting cell growth up to 10 μM. We identified two lysophospholipid derivatives, THZ-2 and THZ-3, that potently inhibited LPA (10 μM)-induced cell growth in PC-3, DU 145, PPC-1 and TSU-Pr1, but not LNCaP, prostate cancer cell lines. IC50 values in the presence of LPA were approximately one-half of those observed in the absence of LPA, suggesting that these analogs inhibit prostate cancer cell growth through an LPA-mediated mechanism. However, activity of these two derivatives in RH7777 cells was equivalent regardless of the presence of LPA. Studies to identify the cytotoxic mechanism of these analogs are ongoing in our laboratory. Supported by a grant from the USAMRMC (#PC010431)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]