HIF-1 dependent reversal of cisplatin resistance via anti-oxidative nano selenium for effective cancer therapy

Abstract

The clinical efficacy of cisplatin (DDP) treatment is largely limited by cisplatin resistance, which is related to the activation of hypoxia-inducible factor 1 (HIF-1). The HIF-1 activation can be induced by low oxygen availability as well as chemotherapeutics in a reactive oxygen species (ROS) dependent manner. Here, instead of the traditional ROS elevation strategy, we designed a chitosan-coated selenium/DDP (CSP) nanoparticle to deplete ROS for circumventing acquired cisplatin resistance. The antioxidative selenium nanoparticles were demonstrated to eliminate cisplatin-induced ROS, and further prevent HIF-1 activation accompanied with cisplatin treatment. A series of cisplatin resistance-associated proteins including glutamate-cysteine ligase modifier subunit (GCLM) and multidrug resistance-associated proteins (MRPs) expression were downregulated in a HIF-1α-dependent manner. And in vitro and in vivo experiments showed that CSP nanoparticles exhibited enhanced antitumor efficacy to cisplatin-resistant A549/DDP lung cancer cell lines and xenografts. These results proved that the side effects of treatment-induced ROS in HIF-1 activation and cisplatin-resistance could be significantly reversed by a selenium nanovehicle, which may possess broader applications in ROS-mediated resistance or other ROS-involved diseases.