Abstract 769: Regulation of drug metabolizing enzyme and transporter gene expression by dietary and chemopreventive phytochemicals in breast cancer

Breast cancer is a leading cause of cancer-related death among American women. The etiology of majority of breast cancers is multifactorial, of which 95% is environmental and hormonal. Polycyclic aromatic hydrocarbons (PAHs) are commonly found in our environment and appear to be carcinogenic by genotoxic mechanisms. The taxanes are the most unique and successful chemotherapeutic agents used for the treatment of breast and ovarian cancer. However, multi-drug resistance (MDR) is one of the primary obstacles for successful chemotherapy. Drug metabolizing enzymes (DMEs) and transporters play important roles in modulating drug absorption, distribution, metabolism, and elimination. The regulation of gene expression of DMEs and transporters has potential impact on drug interactions of many therapeutic agents. P-glycoprotein (P-gp), Pregnane X receptor (PXR), and CYP3A are associated with MDR in breast cancer chemotherapy. Taxanes induce CYP3A by activating PXR-mediated transcription and enhance P-gp mediated drug clearance in human mammary tumor cells. Recent studies involving drug-phytochemical interactions, in addition to interactions among dietary micronutrients, indicate possibilities for improved therapeutic strategies. It is estimated that roughly 50% of cancer patients use some kind of dietary supplements. In the present study, we evaluated the ability of dietary and chemopreventive phytochemicals (curcumin and sulforaphane) on reversal of MDR induced by taxanes (paclitaxel and docetaxel). We also assessed the effects of dietary phytochemicals and taxanes, alone or in combination, on the gene expression of various DMEs, transporters, and receptors in female C57BL/6J mice exposed to the environmental PAH, 7, 12-dimethylbenz(a)anthracene (DMBA). The dietary phytochemicals suppressed the hepatic and mammary gene expression of Phase 1 (CYP1A1, 1B1) DMEs and elevated the levels of Phase 2 (NQO1) DMEs. The hepatic gene expression of CYP3A11, PXR, aryl hydrocarbon receptor and mammary gene expression of P-gp were induced in female mice exposed to DMBA and chemotherapeutic drugs (paclitaxel and docetaxel). Administration of curcumin and sulforaphane inhibited the induced gene expression levels significantly. Treatment of mice with a combination of curcumin and sulforaphane was more effective compared to treatment with either curcumin or sulforaphane alone. The differential regulation of gene expression levels reveal the potential of phytochemicals to reverse MDR in breast cancer chemotherapy. These studies will help in development of effective pharmacotherapeutic based strategies for preventing and treating human breast cancer. The studies will also lead to the development of novel combination drugs that can be used for successful chemotherapy of breast cancer in women. Citation Format: Sudha Kondraganti, Lihua Wang, Weiwu Jiang, Bhagavatula Moorthy. Regulation of drug metabolizing enzyme and transporter gene expression by dietary and chemopreventive phytochemicals in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 769. doi:10.1158/1538-7445.AM2014-769