Abstract 2142: Plumbagin, a medicinal plant-derived naphthoquinone, inhibits the growth of docetaxel resistant prostate cancer cells via inhibition of the expression of P-glycoprotein and NF-kB activation

Abstract

Abstract Prostate cancer (PCa) is one of the leading causes of death in men across the world. Despite the initial success of androgen ablation therapy, resistance to anti-androgen therapy manifests by progression to castration resistant prostate cancer (CRPC), which is the end stage that accounts for the majority of PCa patient deaths. Docetaxel (DTX) is an approved drug for the treatment of CRPC. However, development of DTX resistance and toxicity are the major limitations in the use of DTX in the treatment of CRPC. Now we investigated to determine whether these limitations may be overcome by combining DTX with plumbagin (PL). PL is a quinoid constituent isolated from the root of Plumbago zeylanica L. The roots of Plumbago zeylanica L. have been used in Indian medicine for more than 2500 years for treatment of various ailments. We were the first to report that PL inhibits the growth and PCa metastasis. Now we present that PL: 1) sensitizes CRPC cells to DTX and thus reduces its effective therapeutic dose to prevent DTX resistance and toxicity, and 2) inhibits the viability and growth of DTX resistant cells (22Rv1R). In combination therapeutic experiments, the effects of different concentrations of PL (0, 1.0, 2.0, and 5.0 μM) alone or in combination with DTX (0.25 nM and 0.5 nM) on colony formation in 22Rv1 and C4-2 prostate cancer cells, was determined. Combined treatment of PL and DTX has more than additive inhibitory effects on colony formation. This synergism of PL and DTX on colony formation can be explained on the basis of unique mechanism of action of PL and DTX. PL-induced inhibition of PCa growth and metastasis involves inhibition of the expression of multiple targets including PKCϵ, which correlates with the aggressiveness of PCa and plays roles in both androgen independent androgen receptor (AR) activation and promotion of PCa cell survival. DTX targets microtubules, impairs AR signaling, and inhibits cell division. To determine the effects of PL on DTX resistant PCa cells, we established DTX-resistant 22Rv1 cell line (22Rv1R). 22Rv1R overexpresses multidrug resistant protein 1 (MDR1, also known as P-glycoprotein). MDR1 is overexpressed in many tumors and thus causing intrinsic drug resistant. Transcription factor NF-KB, which is linked to cell proliferation and survival, is also activated in 22Rv1R. PL inhibited the colony forming efficiency of 22Rv1R cells which accompanied inhibition of MDR1 expression and NF-KB activation. In summary, the results presented here and the ones reported by us previously with preclinical mouse models (TRAMP and PTEN knockout mice) of PCa indicate that PL has the potential to prevent as well as treat PCa. PL is a potential natural agent worthy of investigation for prevention and treatment of human PCa. (Support: NIH grant CA102431). Citation Format: Ashok Singh, Anupama Singh, Satyamedha Bathula, Saivenkateshkomal Bathula, Ajit K. Verma. Plumbagin, a medicinal plant-derived naphthoquinone, inhibits the growth of docetaxel resistant prostate cancer cells via inhibition of the expression of P-glycoprotein and NF-kB activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2142.