alpha2beta1 Integrin specific inhibitor BTT-3033 promotes paclitaxel-induced apoptosis in human ovarian cancer cells

Abstract

BACKGROUND AND PURPOSE: The new plan of using molecular targeted agents in combination with cytotoxic drugs may represent a promising strategy to increase the efficacy of chemotherapy. Hence, we examined whether alpha2beta1 integrin-specific inhibitor, BTT-3033, could modulate the susceptibility of OVCAR3 and SKOV3 ovarian cancer cells to paclitaxel (PTX). EXPERIMENTAL APPROACH: Ovarian cancer cell lines were treated with BTT-3033 and different concentrations of PTX. To determine the mechanisms involved in the PTX/BTT-3033 combination-induced cell death, cell viability, apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and caspase-3 activity were evaluated. FINDINGS/RESULTS: Both BTT-3033 (>/= 1 muM) and PTX (>/= 0.01 muM) suppressed the proliferation of OVCAR3 and SKOV3 cells in a concentration-related manner. Pretreatment with BTT-3033 (1 muM), followed by PTX-induced synergistic antiproliferative effects, decreased the IC(50) values of PTX from 0.45 to 0.03 muM in OVCAR3 and 0.35 to 0.02 muM in SKOV3 cells. All of the coefficients of drug interaction for various PTX and BTT-3033 combinations were found to be less than 1. Moreover, PTX/BTT-3033 combination induced more apoptotic cells (from 4.2 to 87.0 in OVCAR3 and 2.4 to 88.5 in SKOV3) than PTX alone. Combination therapy also decreased MMP and increased the caspase-3 activity. Additionally, we found that the PTX/BTT-3033 combination enhanced ROS production in OVCAR3 and SKOV3 cells. CONCLUSION AND IMPLICATIONS: BTT-3033 has demonstrated the ability to enhance the susceptibility of ovarian cancer cells to PTX by inducing MMP loss, ROS production, and mitochondrial apoptosis, therefore this combination therapy might represent a promising strategy for ovarian cancer treatment.