Abstract 3196: Antitumor effect of a Compound A, a derivative of a naturally occurring rotenoid deguelin, by inhibition of ATP binding to heat shock protein 90

Abstract

Despite several decades of intensive efforts to develop anti-cancer drugs and therapeutic strategies, lung cancer is still one of the main causes of cancer-related deaths worldwide. Deguelin, a natural plant product, has shown anti-cancer activities in skin, colon, breast and non-small cell lung (NSCLC) cancers. However, the potential side effects of deguelin could be an obstacle to its use in clinic. In the current study, we aimed to develop a derivative of deguelin with reduced potential side effects. We have synthesized a novel deguelin analog, compound A, and evaluated its effects on cancer and normal bronchial epithelial cell proliferation, survival, and colony formation by the MTT, FACS, and/or anchorage-dependent and -independent colony forming assays. Mechanisms underlying anti-tumor effects of compound A were investigated by Western blot, and RT-PCR. Treatment with compound A inhibited cancer cell proliferation and colony formation, promoted cell cycle arrest and induced apoptosis. Compound A also suppressed the expression of HIF-1α protein and its target gene, VEGF, in NSCLC cells. Administration of compound A to NSCLC xenograft-bearing mice significantly decreased tumor growth by inhibiting tumor angiogenesis and by inducing apoptosis. In its action mechanism, compound A was involved in binding to the ATP-binding pocket of HSP90, leading to the suppression of HSP90 function. These collective results suggest that a novel deguelin derivative, compound A, has a strong potential as an anti-cancer drug. Citation Format: Su-Chan Lee, Ju-Sung Lee, Seung-Yeob Hyun, Hoon Choi, Hongchan An, Kyu-Won Kim, Young-Ger Suh, Ho-Young Lee. Antitumor effect of a Compound A, a derivative of a naturally occurring rotenoid deguelin, by inhibition of ATP binding to heat shock protein 90. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3196. doi:10.1158/1538-7445.AM2014-3196