Histone deacetylase inhibitor panobinostat potentiates the anti-cancer effects of mesenchymal stem cell-based sTRAIL gene therapy against malignant glioma.

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.

• Authors: Seung Ah Choi, Chanhee Lee, Pil Ae Kwak, Chul-Kee Park, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Seung-Ki Kim
• Journal: Cancer letters (Cancer Lett) Vol. 442 Pg. 161-169 (02 01 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30367915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor Decoy Receptors
• Panobinostat

Topics

• Adipose Tissue (cytology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Survival (drug effects)
• Chemotherapy, Adjuvant
• Coculture Techniques
• Female
• Genetic Therapy (methods)
• Glioma (drug therapy, genetics, metabolism, pathology)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Panobinostat (pharmacology)
• Phenotype
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Tumor Necrosis Factor Decoy Receptors (metabolism)
• Xenograft Model Antitumor Assays