Abstract 840: Enhancement of antitumor effect of platinum complexes by PXR antagonist

Abstract

Abstract The goal of this study was to evaluate the enhancing ability of PXR antagonists for the antitumor effect of platinum complex. Cell lines used in this study were human hepatoma cell line HepG2, human ovarian cancer cell line 2008 and human colon cancer cell line HCT116. Changes in mRNA expression were assessed by real-time RT-PCR, and the ability of apoptosis induction was assessed as caspase-3 activity. Cytotoxicity of platinum complexes was assessed by SRB assay, and IC75 and IC90 values of them were determined. They did not induce apoptosis at IC75 but did it markedly at IC90. Previously, we reported that though apoptosis in HepG2 was induced by IC90 dose of CDDP, addition of a PXR agonist, rifampicin, from 24-hr before treatment and during treatment with CDDP was almost suppressed. Moreover, we found that apoptosis in 2008 and HCT116 induced by IC90 dose of CDDP or oxaliplatin was suppressed by rifampicin. That suggests a nuclear receptor PXR affects on the cytotoxicity of platinum complexes for cancer cells other than HepG2. Ketoconazole (KTZ) and phenethyl isothiocyanate (PEITC) were selected as PXR antagonists that were added with platinum complex. Both drugs at 30 μM induced cytostatic cell growth inhibition in HepG2, 2008 and HCT116 but did not affect on caspase-3 activity compared with control in those cells. When these PXR antagonists at 30 μM were added to cancer cell lines from 24-hr before treatment and during treatment with CDDP at IC75, caspase-3 activity was significantly increased compared with that in CDDP alone. Also, when cells were exposed to CDDP and a PXR antagonist without PXR antagonist pretreatment, caspase-3 activity was increased but the level was reduced compared with that in the combination with pretreatment. Similarly, oxaliplatin in combination with KTZ or PEITC markedly induced apoptosis in HCT116. In HepG2, KTZ reduced the level of MRP2 mRNA. That suggests that pretreatment with KTZ might increase the intracellular platinum content and enhance the cytotoxicity of platinum complex. We concluded that PXR antagonist can be an agent enhancing the antitumor activity of platinum complex, and one of the mechanism is to suppress the expression of the platinum efflux transporter. Citation Format: Shuichi Kishimoto, Erika Bou, Kaho Higashi, Ryosuke Suzuki, Shoji Fukushima. Enhancement of antitumor effect of platinum complexes by PXR antagonist. [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 840. doi:10.1158/1538-7445.AM2014-840