Abstract 680: Antitumor activity of CDDP and nuclear receptor PXR

Abstract

Abstract The goal of this study was to evaluate the effect of the possibility of compound that regulate the function of nuclear receptor as agent enhancing the activity of CDDP. Cell lines used in this study were HepG2 and some CDDP-resistant HepG2 cells that were established in our laboratory. These CDDP-resistant HepG2 cells show IC50 values several times higher than that of HegG2 cells. Changes in gene expression were assessed in RT-PCR assays, and the ability of apoptosis induction was assessed as caspase-3 activity. Gene expressions of nuclear receptors in HepG2 cells after exposure to CDDP were examined over time. Interestingly, IC90 dose of CDDP induced significant reduction in PXR mRNA expression with remarkable apoptosis, but IC50 dose of CDDP did no apoptosis and no significant change in PXR mRNA expression. Also, six established CDDP-resistant HepG2 cells show increased PXR mRNA expression relative to parent HepG2 cells. Therfore, PXR agonist and antagonist were used to elucidate if PXR could modulate the sensitivity of cells to CDDP. HepG2 cells exposured to PXR agonist rifampicin for 24 hr showed increased PXR mRNA expression. In HepG2 cells, pre-exposure to rifampicin followed by exposure to CDDP and coexposure to rifampicin and CDDP reduced induction of apoptosis compared to exposure to CDDP alone. Moreover, almost total suppression of apoptosis induced by CDDP was achieved by pre-exposure for 48 hr followed by coexposure to rifampicin for 24 hr. PXR antagonist leflunomide caused a slight enhancement in apoptosis induced by CDDP in HepG2 cells and a significant enhancement in apoptosis induced by CDDP in CDDP-resistant HepG2 cells. We concluded that nuclear receptor PXR is an important factor which regulates the expression of genes that affect on the antitumor activity of CDDP and that PXR antagonist can be a candidate as an agent augmenting the antitumor activity of CDDP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 680. doi:10.1158/1538-7445.AM2011-680