Abstract C39: Docetaxel-induced growth and cell cycle phenotypes in prostate stromal cells

Abstract

Abstract Background: Docetaxel (D) is a clinically used front-line chemotherapeutic agent for castration resistant advanced prostate cancer. However, its long-term benefits are limited with most patients eventually progressing because of inherent or acquired drug resistance. The treatment of advanced prostate cancer is a significant challenge and there are no effective treatments that stably suppress the disease. The mechanisms behind resistance to Docetaxel are not fully understood. Since in vivo Docetaxel cytotoxicity is directed not only to cancer cells, we hypothesize that the response of prostate stromal cells exposed to chemotherapeutic agents could modify drug response or therapeutic outcome in prostate cancer. One of cellular responses to chemotherapy is NF-kB activation and inflammatory signaling. NF-κB activation has been proposed as an important event in PCa development, castration-resistant progression and resistance to chemotherapy. Objective: In this study, we examined the response of prostate stromal (WPMY- 1) cells to Docetaxel. Current Results: Cellular proliferation was analyzed by MTT assay. The IC50 of Docetaxel for WPMY-1 cells was 10nM. Cell cycle profiles were assessed by flow cytometry. The analysis showed that Docetaxel (10-100nM) induced prominent G2-M arrest in these stromal cells within 24 hours, especially in the higher dose ranges. Interestingly lower doses of Docetaxel (10nM), in contrast to higher doses, consistently resulted in accumulation of sub-G1 population (28% 10nM vs 6% in 100nM) of cells suggestive of fragmented DNA associated with apoptotic process. We show that Docetaxel exhibits strong anti-proliferative effects on prostate stromal WPMY-1 cells. Conclusions: These preliminary results show that stromal cells are sensitive to Docetaxel. Why lower doses of the drug induce sub-G1 (apoptotic) accumulation while higher doses preferentially induce G2-M arrest is currently unknown. Future Steps: We will compare responses to D between prostate cancer cells and stromal cells in individual and co-culture models. NF-kB activity following D treatment or radiation, and the expression of genes in NF-kB pathway in D treated cells will be examined. Citation Format: Dominique Gales, Brionna McMcmeans, Temesgen Samuel. Docetaxel-induced growth and cell cycle phenotypes in prostate stromal cells. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C39. doi:10.1158/1538-7755.DISP13-C39