Abstract 5520: A novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), induces apoptotic cell death through mitochondrial cytochrome c release in renal cell carcinoma

Abstract

Introduction: N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) is a novel HDAC inhibitor that shows better pharmacological properties than known HDAC inhibitors. We investigated a therapeutic role and its mechanisms of HNHA in renal cell carcinoma. Methods: Renal cell carcinoma cell lines, Caki-1, A-498, 786-O and UMRC-3 cells were used for in vitro study. Crystal violet assay was used to assess cell growth. Apoptosis was evaluated by TUNEL assay and confirmed by expression of cleaved caspase-3 and caspase-7. Cytochrome c release was evaluated by mitochondria staining. For in vivo study, Caki-1 and A-498 cells were injected (1.0 x 107/mouse) into the dorsal sub-membrane of 6-week-old BALB/C nude mice. Two different drugs were injected at Lethal Dose 50: HNHA, 206 µg/mL and SAHA, 138 µg/mL. Result: HNHA suppressed tumor proliferation in all panels of renal cell carcinoma cells. TUNEL assay and Western blots showed that remarkable apoptosis was induced by HNHA in Caki-1 and A-498 cells. HNHA induced apoptotic cell death by caspase activation and Bcl 2 suppression in renal cell carcinoma in vitro and in vivo. HNHA also caused cytochrome c release from mitochondria through Bax and Bak expression. A primary caspase activation was initiated by cytochrome c release from mitochondria, which is able to induce biochemical reactions, caspase activation and subsequent cell death. Conclusion: HNHA induces more potent apoptotic cell death in renal cell carcinoma in vitro and in vivo than the previous HDAC inhibitors. HNHA-induced apoptosis is mediated by cytochrome c release from mitochondria through induction of Bax and Bak expression in renal cell carcinoma. Citation Format: Kyung Seok Han, Ki Cheong Park, Jeong Yong Jeon, Sang Yong Kim, Dami Song, Woong Kyu Han, Sung Joon Hong. A novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), induces apoptotic cell death through mitochondrial cytochrome c release in renal cell carcinoma. [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 5520. doi:10.1158/1538-7445.AM2014-5520