Abstract 5608: Iron depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma.

Abstract Purpose. Sorafenib is a multiple kinase inhibitor approved for advanced hepatocellular carcinoma(HCC). However, we couldn't get sufficient effect in clinical use compared to other cancers. Iron metabolism and relationship with cancer cells have been studied for a long time. Iron overload is known to associate with an increased risk of HCC, and the recent study suggests that iron depletion can induce anti-cancer effect against HCC. We hypothesized that iron depletion enhance the effect of sorafenib and investigated it. Experimental Design. HepG2 (Human hepatocellular liver carcinoma cell line) was used in this study. We used sorafenib and an oral iron chilator, deferasirox (EXJADE TM). The effects of each agent and combination of both were examined by using cell viability assay. We examined anti-proliferative mechanism in vitro using Flow Cytometry and Western blot analysis. Results. We examined the cell viability of HepG2. Each treatment by sorafenib and deferasirox suppressed the cancer cell proliferation on dose dependent manner. The IC50 values of 48hours of sorafenib was 1.45μM/L,and that of deferasirox was 1.37μM/L. We examined the possibility of combination therapy. The each cell viability of sorafenib 1μM and deferasirox 10μM was 59.4% and 28.1%, the combination one was 21.8%. The combination index was 0.616 in that status, which suggested synergistic effect. To evaluate anti-proliferation mechanism, we performed Flow Cytometry and Western blot analysis. In Flow Cytometry, S and G2/M phase was significantly decreased, which suggested to arrest cell cycle. In Western blot analysis, cyclin D1 was down-regulated. Conclusion. Iron depletion by deferasirox have anticancer effect by alone and a synergistic effect in combination with Sorafenib. This result suggested that iron depletion therapy can be a novel combination chemotherapy for HCC. Citation Format: Shinichi Urano, Toshiaki Ohara, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Masafumi Kataoka, Nouso Kazuhiro, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5608. doi:10.1158/1538-7445.AM2013-5608