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MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-?-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells.

ABSTRACT: Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective inhibition of HDAC6 has been widely discussed for the treatment of hematologic malignancies. We previously identified that MPT0G612 is a novel HDAC6 inhibitor exhibiting a promising antitumor activity against several solid tumors. The purpose of the present study was to evaluate the feasibility and pharmacological mechanisms of MPT0G612 as a potential therapy for CRC patients. Results revealed that MPT0G612 significantly suppresses the proliferation and viability, as well as induces apoptosis in CRC cells. Autophagy activation with LC3B-II formation and p62 degradation was observed, and the inhibition of autophagy by pharmacological inhibitor or Atg5 knockdown enhances MPT0G612-induced cell death. In addition, HDAC6 knockdown reduces MPT0G612-mediated autophagy and further potentiates apoptotic cell death. Furthermore, MPT0G612 downregulates the expression of PD-L1 induced by IFN-? in CRC cells. These results suggest that MPT0G612 is a potent cell death inducer through inhibiting HDAC6-associated pathway, and a potential agent for combination strategy with immune checkpoint inhibitors for the treatment of CRC.

SUBMITTER: Chen MC

PROVIDER: S-EPMC6826904 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells.

Chen Mei-Chuan MC Lin Yu-Chen YC Liao Yu-Hsuan YH Liou Jing-Ping JP Chen Chun-Han CH

Cancers 20191022 10

Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective inhibition of HDAC6 has been widely discussed for the treatment of hematologic malignancies. We previously identified that MPT0G612 is a novel HDAC6 inhibitor exhibiting a promising antitumor ...[more]

PMID: 31652644

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Project description:AIM:Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. METHODS AND RESULTS:We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. CONCLUSION:PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

Dataset Information

MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-?-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells.

Publications

MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells.

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