Abstract 3841: HIF-143, a novel inhibitor of complex III, inhibits pancreatic cancer growth by suppressing reactive oxygen species production and epidermal growth factor signal

Abstract

Abstract Reactive oxygen species have been considered as a therapeutic target for cancer treatment. In this study, we characterized the anticancer activity of novel small molecule inhibitor of cytochrome bc1, HIF-143, in pancreatic cancer. HIF-143 shares common structural moiety with known cytochrome bc1 Qo inhibitors including azoxystrobin and E-α-methoxyacrylate-stilbene. HIF-143 inhibits reduction of cytochrome c by purified mitochondria in the presence of rotenone and induction of reactive oxygen species by hypoxia or epidermal growth factor in cellular context. HIF-143 also suppresses activation of EGFR and downstream ERK and AKT induced by EGF treatment. EGF-induced transcription was also inhibited by HIF-143. Interestingly, these effects were synergistic when combined with EGFR inhibitor such as Erlotinib and Gefitinib. Cell proliferation, survival, and anchorage-independent growth were also synergistically inhibited by HIF-143 and Erlotinib. HIF-143 also inhibited pancreatic tumor growth in BxPC-3 human pancreatic cancer xenograft model. The inhibition of tumor growth was much higher when animals were treated with both HIF-143 and Erlotinib than individual treatment, suggesting synergistic anticancer activity in vivo. In addition, when HIF-143 was combined with Erlotinib and Gemcitabine, anticancer efficacy was increased without the increase of sign of toxicity, showing addition of HIF-143 can give clinical benefit to pancreatic cancer patients. Toxicological study showed that combination of HIF-143 and Erlotinib is safe enough with safety margin higher than 6-fold. These findings suggest that pharmacological targeting of complex III might be a promising approach to treat pancreatic cancer. These results provide scientific rational for testing of HIF-143 in the clinical trial to develop as a novel anticancer drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3841. doi:1538-7445.AM2012-3841