Abstract 3803: Potential role of multidrug resistance associated protein (MRPs) in hypoxia-induced drug resistance of non-small cell lung cancer cells (H460)

Abstract

Abstract H460 is a non-small cell lung cancer (NSCLC) cell with multidrug resistance (MDR) against a variety of anti-cancer drugs such as cisplatin and transforming growth factor-beta (TGF-beta). It has been reported that hypoxia can trigger the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the subsequent production of P-glycoprotein (P-gp, the archetype of MDR associated proteins or MRPs) that eventually lead to chemotherapeutic resistance of various cancer cell lines as well as NSCLC patients. The primary concern of this study was to know would hypoxia promote drug resistance of H460 cells via MRPs (MRP1 and MRP3). The experimental strategies applied were to evaluate the hypoxic impacts upon: 1) the drug resistance of H460 cells against doxorubicin (DOX, a commonly used chemotherapeutic drug in many cancer treatments), using MTT assay; 2) the expression of MRP1, MRP3 and HIF-1alpha of H460 cells in the absence or presence of DOX, using Western blot analysis; 3) the intracellular accumulation of DOX in H460 cells, using flow cytometry. The current results showed that DOX triggered a dose- and time-dependent cell death of H460. A hypoxia-induced DOX resistance was observed in H460 cells. Western blot analysis further showed that DOX-decreased MRP1 was further exacerbated under hypoxic condition that precluded the possible involvement of MRP1 in hypoxia-induced drug resistance. DOX on contrary increased the expression of MRP3. The potential contribution of MRP3 to hypoxia-induced DOX resistance and its role in pumping out of DOX from H460 cells are currently investigated in our laboratory. Finally, hypoxia-induced HIF-1alpha remained still high in the presence of DOX, suggesting a potential role of HIF-1alpha in promoting the DOX resistance of H460. Results from the study can uncover the molecular mechanisms underneath hypoxia-induced DOX resistance of H460 that consequently can lead to therapeutic target(s) for treatment of NSCLC cells (H460). 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 3803. doi:10.1158/1538-7445.AM2011-3803