Abstract 3325: Ginkgetin, a biflavonoid derived from leaves of Ginkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62

Abstract

Abstract Chemotherapeutic drugs in the treatment of non-small-cell lung carcinoma (NSCLC) are usually mediated by induction of apoptosis; this usually results in drug resistant during the therapy. Many compounds from natural resource have been shown to trigger autophagy in promoting cell death, and therefore which could be a novel treatment for cancer. Ginkgetin, a biflavonoid from Ginkgo biloba leaves (Ginkgoaceae), was shown its anticancer effects recently. The leaf of G. biloba is being recorded as a safe herbal drug in Pharmacopoeia from China and Europe. Here, the possible development of ginkgetin as an anticancer drug was demonstrated. Ginkgetin induced the death in A549 (NSCLC) with an IC50 lower than that of cisplatin. This anticancer effect of ginkgetin was also illustrated in NSCLC xenograft nude mice model. Transmission electronic microscope revealed that ginkgetin-induced autophagy was the main cause of cell death. Autophagy inhibitors, 3-methyladenine and chloroquine but not apoptosis inhibitor Z-VAD-FMK, rescued ginkgetin-induced cell death. Reciprocally, the induction of autophagy by rapamycin promoted ginkgetin-induced cell death, as well as the formation of p62-TRAF6-mTOR. During autophagy, p62 is hypothesized to be a target of ginkgetin-induced autophagic cell death. This notion is supported by several lines of evidence. The application of ginkgetin blocked fully the expression of p62 in cultured A549, and in contrast the over expression of p62 reduced ginkgetin-induced autophagy and cell death concomitantly with the decline on autophagosome formation. In parallel, the modulation on p62 expression could regulate Nrf2 activity and ROS level in the presence of ginkgetin. Thus, autophagy could act as an inducer in ginkgetin-induced cell death, and p62 was proposed to be a possible target during this process. Here, ginkgetin exhibited promising anticancer effect in NSCLC via autophagy, a signaling very different to orthodox chemotherapeutic drug cisplatin. Besides, ginkgetin is a phytochemical from G. biloba that is considered as a safe herbal supplement, and no obvious toxicity was observed in xenograft nude mice. Therefore, ginkgetin is proposed to be a potential compound for the development of novel anticancer drug. Acknowledgements: This study was supported by Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), GRF (663012, 662713, M-HKUST604/13), TUYF15SC01 and Foundation of The Awareness of Nature (TAON12SC01) to Karl Tsim. Citation Format: Jian Shu Lou, Cathy Bi, Gallant Chan, Tina Dong, Karl Tsim. Ginkgetin, a biflavonoid derived from leaves of Ginkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3325. doi:10.1158/1538-7445.AM2017-3325