Abstract
The intracellular level of reactive oxygen species (ROS) is closely associated with chemosensitivity of cancer cells. Overexpression of ATP binding cassette transporter MRP1 is correlated with resistance to platinum drugs. In this study, we tested the hypothesis that emodin, a potent ROS generator, may increase sensitivity of cisplatin-(cDDP-) resistant ovarian carcinoma cells to cDDP cytotoxicity via ROS-mediated suppression of MRP1 expression. Using the isogenic pair of the human ovarian carcinoma cell line COC1 and its cDDP resistant variant COC1/DDP, we found that ROS level in the cDDP-sensitive ovarian cancer cells was significantly higher than that in the cDDP-resistant cells. Emodin enhanced ROS production in COC1/DDP cells and consequently sensitized them to cDDP-induced apoptosis. These effects were reversed by addition of the antioxidant N-acetyl-L-cysteine (NAC). Cotreatment with emodin and cDDP inhibited the tumor growth in vivo by increasing tumor cell apoptosis. The emodin-enhanced cDDP cytotoxicity was attributable to downregulation of multidrug resistance-related protein 1 (MRP1) expression. Together, these results suggest that emodin could act as an adjunct to enhance the anticancer effect of cDDP likely through ROS-related downregulation of MRP1 expression, and may be of therapeutic potential in cDDP-refractory ovarian carcinomas.
Highlights
Ovarian cancer (OC), consisting predominantly of carcinomas, is the most lethal gynecologic malignancy and currently ranks fifth in causing cancer-related deaths among women [1]
Our present study was based on the hypothesis that emodin can sensitize platinumresistant ovarian cancer cells to cDDP-induced apoptosis through elevation of intracellular reactive oxygen species (ROS) and downregulation of the GSH conjugate exporter multidrug resistance-related protein 1 (MRP1)
To determine whether cDDP resistance was a result of altered intracellular ROS levels, ROS was measured in COC1 and COC1/DDP cells
Summary
Ovarian cancer (OC), consisting predominantly of carcinomas, is the most lethal gynecologic malignancy and currently ranks fifth in causing cancer-related deaths among women [1]. Increase in ROS production is known to enhance cytotoxic effects of various anticancer drugs whereas cells with a lower ROS level appear less responsive to chemotherapy [11]. In this regard, manipulation of oxidation-reduction (redox) status of cancer cells to sensitize them to chemotherapeutic drugs is being exploited as a potential therapeutic and resistance-circumventing strategy. Our present study was based on the hypothesis that emodin can sensitize platinumresistant ovarian cancer cells to cDDP-induced apoptosis through elevation of intracellular ROS and downregulation of the GSH conjugate exporter MRP1
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