Histone deacetylase inhibitor panobinostat potentiates the anti-cancer effects of mesenchymal stem cell-based sTRAIL gene therapy against malignant glioma. (1st February 2019)

• Record Type: Journal Article
• Authors: Choi, Seung Ah; Lee, Chanhee; Kwak, Pil Ae; Park, Chul-Kee; Wang, Kyu-Chang; Phi, Ji Hoon; Lee, Ji Yeoun; Chong, Sangjoon; Kim, Seung-Ki
• Is Part Of: Cancer letters. Volume 442(2019)
• Page Start: 161
• Page End: 169
• Publication Date: 2019-02-01
• Subjects: hAT-MSC.sTRAIL -- Panobinostat -- Malignant glioma -- Antitumor effect -- Apoptosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.10.012
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Human adipose tissue-derived mesenchymal stem cells expressing the secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (hAT-MSC.sTRAIL) have demonstrated therapeutic activity against various tumors in preclinical studies. However, the limited expression of TRAIL death receptors remains a challenge. We evaluated the therapeutic efficacy of panobinostat in enhancing the sensitivity of hAT-MSC.sTRAIL-mediated apoptosis in malignant glioma. Panobinostat effectively inhibited all malignant glioma cells (IC50, 0.03–0.23 μM), enhancing the expression of DRs, but not in hAT-MSCs. Combined treatment with hAT-MSC.sTRAIL and panobinostat significantly suppressed cell viability and enhanced apoptosis. In a diffuse intrinsic pontine glioma (DIPG) mouse model, the combined treatment induced decreases in tumor volume and prolonged survival. Our study demonstrates that panobinostat enhances the expression of TRAIL DRs and potentiates the anti-cancer effects of hAT-MSC.sTRAIL. Highlights: hAT-MSC.sTRAIL have demonstrated the anti-cancer activity against malignant gliomas. The low expression level of TRAIL death receptors (DR) is challenged in malignant glioma. Treatment of hAT-MSC.sTRAIL with panobinostat showed induction of DR expression. Combined treatment can target the epigenetic dysregulation in malignant glioma cells. This study provides a novel strategy of MSC based gene therapy with HDACi against malignant glioma.