Cisplatin (CDDP) has been recognized as an important antitumor agent since its introduction into clinical trials about three decades ago. However, many patients eventually relapse and develop resistance, representing a major limitation of platinum-based chemotherapy. Multiple mechanisms have been proposed to account for the resistance to cisplatin; and numerous studies have demonstrated that exposing cultured cells to cisplatin led to the development of CDDP resistance with concomitant increased of glutathione (GSH) levels and elevated expression of the rate-limiting enzyme of its biosynthesis, gamma glutamylcysteine synthetase (g-GCS) which consists of a heavy (catalytic) subunit (g-GCSh) and a light (regulatory) subunit. These observations led to the supposition that elevated GSH levels are associated with CDDP resistance. However, we found that elevated GSH levels (1.5- to 3.9-fold) in three g-GCSh-transfected human small cell lung cancer cell lines (SCLC) and two g-GCSh transfected rat hepatoma cell lines all exhibited elevated sensitivities to cisplatin (4.2- to 10-fold reduction in IC50). All the transfected cells exhibited elevated rates of CDDP transport due to upregulation of copper transporter (hCtr1); whereas expression of copper exporters ATP7A and ATP7B were only marginally increased. hCtr1 and ATP7A and ATP7B have been demonstrated to be cisplatin importer and exporters, respectively. Upregulation of hCtr1 in the transfected cells were not due to reduced reactive oxygene species (ROS)levels by elevated GSH expression, because SCLC cells treated with catalase which reduces intracellular ROS levels did not upregulate hCtr1 expression. Our results suggest that increased GSH levels per se are not responsible for cisplatin resistance is the drug-treated cell lines as previously thought. Rather, it may reflect a stress response phenomenon, because g-GCSh is a stress response gene.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA