Abstract 2323: Iron chelator contributes to anti-angiogenic therapy via selective induction of VEGF-A

Abstract

Abstract [Introduction] Iron is essential for cancer to survive. Cancer cell is suppressed to proliferate under the iron depletion condition using iron chelator. However, only iron depletion can't suppress tumor growth completely. The reason is that cancer cell has abilities to escape the severe environment. These abilities are known as angiogenesis, migration, etc. Thus, to inhibit not only cancer cell proliferation but also these abilities are important for anti-cancer therapy. Bevacizumab, an antibody against vascular endothelial growth factor, is the first clinical anti-angiogenic drug. It's used for many kinds of cancer patients and revealed clinical benefit. According to spread widely in use, the resistance of Bevacizumab has been recognized. Recently, patients in resistance of Bevacizumab were reported to be high concentration of PIGF, VEGF-C and VEGF-D. On the other hand, we have demonstrated a synergistic therapeutic effect of iron depletion on anti-angiogenic therapy for human cancer in this meeting. In vitro study, iron chelator was used to simulate the iron depletion condition. Our result showed that iron depletion has anti-proliferative effect and induction of VEGF-A. Therefore, Bevacizumab revealed a synergistic therapeutic effect in iron depletion condition. In this study, we hypothesized that iron chelation therapy has anti-proliferative effect and induction of only VEGF-A(not PIGF, VEGF-C and VEGF-D). [Matherials and Methods] A549, H1299 NSCLC cell lines were used. Iron chelator deferasirox and deferoxamine were prepared to simulate iron depletion condition. Cell viability was determined by WST-1 assay. To determine induction of iron chelator, PIGF, VEGF-A, C, D ELISA assays were performed. In vivo Bevacizumab administration study, we used A549 subcutaneous tumor xenograft mice(n=5/group). Deferasirox(50mg/kg) was administrated orally 5days in a week. Bevaicuzmab(5 mg/kg) was administrated twice a week intravenously. [Results] Iron chelator suppressed cancer cell proliferation and induced only VEGF-A(not PIGF, VEGF-C and VEGF-D). VEGF-A was induced by iron chelator in dose dependent manner. Deferasirox revealed synergistic anti-tumor effect with Bevacizumab in vivo study. [Conclusion] Iron chelator contributes to anti-angiogenic therapy via selectively inducing VEGF-A. Iron chelator can be a new therapeutic strategy of Bevacizumab combination therapy. 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 2323. doi:1538-7445.AM2012-2323