IDDF2019-ABS-0072 Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma. (June 2019)

• Record Type: Journal Article
• Authors: Jin, Huilin; Liao, Junbin; Xu, Lixia; Zhou, Qi; Peng, Sui
• Is Part Of: Gut. Volume 68(2019)Supplement 1
• Page Start: A49
• Page End: A49
• Publication Date: 2019-06
• Subjects: Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2019-IDDFAbstracts.86
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Both apatinib and radiotherapy showed a valid but limited therapeutic effect in hepatocellular carcinoma (HCC). This study aimed to investigate the potential clinical utility of apatinib as a radiosensitizer and its mechanism in HCC. Methods: Four human HCC cell lines including SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or apatinib plus irradiation. For in vitro study, colony formation assay, flow cytometry of cell cycle and apoptosis, immunofluorescence-based detection of nuclear γ-H2AX foci, immunohistochemistry, TUNEL assay, western blot and RNA sequencing were performed . For in vivo experiment, xenograft models generated from nude mice bearing subcutaneous HCC tumors were used to assess the impact on tumor growth of apatinib plus irradiation compared with monotherapies. Results: Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines with sensitivity enhancement ratio (SER) in SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B, respectively. Immunofluorescence and western blot displayed that nuclear γ-H2AX foci exhibited more and lasted longer in the combination treatment group than that in monotherapies groups, indicating apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. RNA sequencing and western blot detection revealed that apatinib radiosensitized HCC cells via suppression of radiation inducing PI3K/AKT pathway, which was further confirmed by using PI3K or AKT inhibitors. Moreover, in vivo study indicated xenograft tumor growth was significantly decreased in the combination treatment group compared with mono apatinib or irradiation group. Conclusions: Our results demonstrate that apatinib could sensitize HCC radiotherapy through inhibiting PI3K/AKT signaling pathway. Apatinib may have potential as a radiosensitizer to augment the clinical therapeutic effect of radiotherapy in HCC.