Abstract B13: New drug repositioning of low-dose pegylated IFN-alpha in combination with BH3 interacting domain death agonist gene and radiation therapy as a cancer treatment regimen

Abstract

Abstract Purpose: Chemotherapy and radiation therapy (RT) are frequently selected for cancer treatment regimens, however they have limitations. Further regimens should be considered to overcome difficulties in cancer treatments. We have reported that interferon (IFN)-alpha induces in vitro cell death mediated by BH3-interacting domain death agonist (BID). However, low-dose pegyrated (PEG)-IFN-alpha, which suggests the possibilities of better adherence and fewer side effects, is clinically approved for treatment of hepatitis C, but not for that of any tumors. RT may also induce cell death. Here we assessed in vivo antitumor effects of pIRES-hBID (BID) transfection followed by low-dose PEG-IFN-alpha and RT (BID+IFN+RT). Experimental Procedures: A549 human lung carcinoma cells are resistant to both IFN-alpha and RT. In the present study, BID and low-dose PEG-IFN-alpha were administered into nude mice bearing subcutaneous A549 xenografts. The mice were then irradiated with 3 Gy gamma ray. These treatments were performed once a week for 4 weeks. Results: No body weight-loss was observed following any treatments. Immunohistochemistry demonstrated significantly less intranuclear localization of BID protein induced by BID alone and BID+IFN compared to mock alone and BID alone, respectively. These results suggest that each of BID and low-dose PEG-IFN-alpha affected BID translocation. Assessment of tumor volume indicated synergistic effects of growth inhibition induced by BID+IFN+RT. Electron microscopic examination of tumors on Day 56 demonstrated not only fragmented plasma membranes and nuclei but also cytoplasmic vesicles with degraded contents induced by BID+IFN+RT, indicating that low-dose PEG-IFN-alpha and RT following BID may induce both apoptotic and non-apoptotic cell death including autophagy and/or necrosis. Conclusions: Even low-dose PEG-IFN-alpha likely had antitumor effects when combined with BID and RT, suggesting the possibility of new drug repositioning of PEG-IFN-alpha. Consequently, BID+IFN+RT may be a promising regimen for treating tumors that are resistant to both IFN-alpha and RT. Citation Format: Takaya Tsuno, Shohei Kanno, Iwata Ryoichi, Noboru Tanigawa, Tetsuya Ueba. New drug repositioning of low-dose pegylated IFN-alpha in combination with BH3 interacting domain death agonist gene and radiation therapy as a cancer treatment regimen [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B13.