Abstract 1681: Iron chelation therapy increased the anticancer effect of sorafenib in hepatocarcinoma

Abstract

Abstract [Purpose] Iron overload is known to associate with the progression of chronic hepatitis and the increase risk of hepatocellular carcinoma (HCC). We have reported that iron depletion inhibited the cancer cell proliferation and reciprocally induced angiogenesis. Anti-angiogenic drug synergistically enhanced the anti-tumor effect in iron depletion condition. Sorafenib is molecular-targeting drug with anti-angiogenic effect in HCC. We hypothesized that iron depletion also enhanced the effect of sorafenib and investigated it. [Experimental Design] HepG2 and HLE (Human HCC cell line) were used in this study. We used sorafenib (NexavarTM) and an oral iron chilator, deferasirox (EXJADETM). The anti-cancer effect and mechanism were determined using cell viability assay, VEGF ELISA, Flow Cytometry, Western blot analysis and in vivo subcutaneous tumor model. In clinical cases, we retrospectively analyzed the relationship between sorafenib response and serum iron-related makers(n=58). [Results] In HepG2 and HLE cells, deferasirox suppressed the cancer cell proliferation by itself and increased the suppression of sorafenib. Deferasirox increased VEGF secretion of supernatant on dose dependent manner. In the analysis of combination therapy, cell cycle arrest and apoptosis was enhanced in the combination therapy by down-regulation of cyclinD1 and cyclinE and up-regulation of cleaved PARP. The suppression of HepG2 subcutaneous tumor was enhanced in the combination therapy. In clinical cases, sorafenib prolonged overall survival in TIBC high and Ferritin low group. [Conclusion] Iron depletion by deferasirox increased the anti-cancer effect of sorafenib in vitro and in vivo experiments. In clinical cases, sorafenib was also effective in iron deficient patients. These results suggested that iron depletion therapy can be a novel combination chemotherapy with sorafenib for hepatocarcinoma patients. Citation Format: Shinichi Urano, Toshiaki Ohara, Ryoichi Katsube, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Kazuhiro Nouso, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron chelation therapy increased the anticancer effect of sorafenib in hepatocarcinoma. [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 1681. doi:10.1158/1538-7445.AM2014-1681