Prostate cancer inhibitory activity of a novel dual inhibitor, EL102, in combination with docetaxel, and its effects on MDR1-mediated drug resistance in vitro.

Abstract

e15126 Background: EL102 is a dual-action drug promoting apoptosis and inhibiting angiogenesis. It exerts its action though the inhibition of Hif1a induced hypoxic signalling and induction of the Caspase 3/7 apoptotic cascade. The drug has equal activity in normoxia and hypoxia indicating it may be equally active in these different tumor compartments. We tested its ability to circumvent chemotherapeutic drug resistance. Methods: We assessed the ability of EL102 to inhibit prostate cancer cell proliferation and motility in vitro, calculating IC50s for CWR22, 22Rv2, PC3 and DU145 prostate cancer cell lines, comparing sensitivity between androgen dependent, androgen independent and metastatic prostate cancer. Additionally we assessed the activity of EL102 in combination with docetaxel in vitro and in murine CWR22 xenografts. The ability to overcome MDR1 and BCRP mediated drug resistance was also tested using DLKP drug resistant variants which exhibit 200 fold resistance to doxorubicin, docetaxel, paclitaxel and vincristine. Results: We found that prostate cancer cell lines are sensitive to EL102 with IC50s in the region of 10-50nM. Of particular interest was the identical sensitivity of the androgen independent 22Rv1 and its androgen dependent parent CWR22, suggesting ability to overcome hormone refractory prostate cancer. Additionally we demonstrate dose response for inhibition of cell motility in metastatic DU145. In CWR22 murine mouse models treatment with EL102 resulted in decreased tumor volume compared to control. A docetaxel and EL102 combination arm demonstrated the greater inhibition of tumor growth than EL102 or docetaxel alone. The lung cancer cell line DLKP, its drug resistant variants DLKPA (MDR1 overexpressing) and DLKPMitox (BCRP overexpressing) were equally sensitive to EL102 indicating that EL102 is not a substrate for MDR1 or BCRP. Conclusions: EL102 is a potential therapeutic for the treatment of prostate cancer, in particular in combination with docetaxel, and exhbibits the potential to overcome drug resistane. Future studies will include the efficacy of this drug in prostate cancer metastatic mouse models.