Reversal of multi drug resistance to taxanes by P-glycoprotein modulating chemopreventive phytochemicals

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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), commonly found in our environment are carcinogenic by genotoxic mechanisms. Some of the environmental chemicals mimic the properties of estrogen and may exert a hormonal influence on breast cancer. These chemicals share a common mode of action by activating the estrogen receptor (ER) and thereby elicit estrogenic responses. In addition to being estrogenic, xenoestrogens interact with xenobiotic- and drug-metabolizing CYP forms, including members of the CYP1A and CYP3A subfamilies.

The regulation of gene expression of various drug metabolizing enzymes (DMEs) has potential impact on drug interactions of many therapeutic agents. DMEs include phase I, phase II metabolizing enzymes as well as phase III transporters. P-glycoprotein (P-gp), Pregnane X receptor (PXR), and CYP3A4 are associated with multi drug resistance (MDR) in breast cancer chemotherapy. Taxanes are among the most unique, and successful chemotherapeutic agents used for the treatment of breast and ovarian cancer. Taxanes induce CYP3A by activating PXR-mediated transcription and enhance P-gp mediated drug clearance in human mammary tumor cells. The abundant and inexpensive chemopreventive dietary phytochemicals are being explored as P-gp modulators for the reversal of MDR to breast cancer chemotherapeutic drugs.

In the present study, we evaluated the effects of PAHs and chemopreventive dietary phytochemicals on the expression of liver and mammary CYP3A11, PXR, and P-gp activities. In wild type (C57BL/6J) female mice treated with 7,12-dimethylbenz(a)anthracene (DMBA), the apoprotein contents (Western blotting), and mRNA (Real time RT-PCR) expression of CYP3A11 and PXR genes were elevated in liver tissues of mice exposed to taxanes. The CYP3A11 and PXR gene expression was down regulated when the mice were treated with both taxanes and phytochemicals. The mammary P-gp expression was elevated in mice treated with taxanes compared to controls. Administration of phytochemicals along with taxanes inhibited the P-gp expression significantly showing a potential to reverse multi drug resistance. Induction of specific DNA adducts was observed in liver and mammary tissues of mice treated with PAHs and phytochemicals.

These studies show a potential for development of dietary phytochemical as a therapeutic drug to be used in combination chemotherapy for treating human breast cancer.