Abstract 5454: Wogonin overcomes cisplatin resistance of head and neck cancer by targeting antioxidant defense mechanisms

Abstract

Abstract Background: Cisplatin is a first-line chemotherapeutic agent for head and neck cancer (HNC). However, the main limitation to clinical usefulness of cisplatin is the high incidence of chemoresistance causing one of major failures in cancer management. This may suggests the necessity of combination therapies of cisplatin with other drugs to circumvent chemoresistance. Wogonin, one of major natural flavonoids, is known to reverse multidrug resistance in several types of cancers, however, which has been rarely tested in HNC cells. Therefore, the present study investigated the ability and molecular mechanisms of wogonin overcoming cisplatin resistance in HNC cells. Methods: Two cisplatin-resistance HNC cell lines (AMC-HN4R and -HN9R) and their parental and other human HNC cell lines were used. The effect of wogonin, alone and in combination with cisplatin, was assessed in HNC cells and normal cells by measuring cell viability, cell cycle and death assays, reactive oxygen species (ROS) production, and protein expression, and in preclinical tumor xenograft mouse models. Results: Wogonin selectively killed HNC cells but spared normal cells. It inhibited NF-E2-related factor 2 (NRF2), P-glycoprotein, and glutathione S-transferase P (GSTP), overexpressed in cisplatin-resistant HNC cells, resulting in the increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Wogonin also induced selective cell death by targeting the antioxidant defense mechanisms enhanced in the resistant HNC cells and subsequently, effectively activating cell death pathways involving PUMA and PARP. Therefore, wogonin significantly sensitized the resistant HNC cells to cisplatin in vitro and in vivo. Conclusions: Wogonin might be the promising anticancer candidate by inducing ROS accumulation and selective killing HNC cells, thus contributing to overcome the cisplatin-resistance of HNC cells. Citation Format: Ji Won Kim, Eun Hye Kim, Jin Young Park, Minsu Kwon, Jong-Lyel Roh. Wogonin overcomes cisplatin resistance of head and neck cancer by targeting antioxidant defense mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5454. doi:10.1158/1538-7445.AM2015-5454