摘要

Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancerassociated 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-Γ 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.
原文英語
文章編號1617
期刊Cancers
11
發行號10
DOIs
出版狀態已發佈 - 十月 2019

指紋

Colorectal Neoplasms
Apoptosis
Ligands
Autophagy
Cell Death
Neoplasms
Pharmacology
Histone Deacetylases
Hematologic Neoplasms
Cause of Death
Therapeutics
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

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title = "MPT0G612, a novel HDAC6 inhibitor, induces apoptosis and suppresses ifn-Γ-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 cancerassociated 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-Γ 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.",
keywords = "Apoptosis, Autophagy, Colorectal cancer, HDAC6, PD-l1",
author = "Chen, {Mei Chuan} and Lin, {Yu Chen} and Liao, {Yu Hsuan} and Liou, {Jing Ping} and Chen, {Chun Han}",
year = "2019",
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T1 - MPT0G612, a novel HDAC6 inhibitor, induces apoptosis and suppresses ifn-Γ-induced programmed death-ligand 1 in human colorectal carcinoma cells

AU - Chen, Mei Chuan

AU - Lin, Yu Chen

AU - Liao, Yu Hsuan

AU - Liou, Jing Ping

AU - Chen, Chun Han

PY - 2019/10

Y1 - 2019/10

N2 - Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancerassociated 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-Γ 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.

AB - Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancerassociated 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-Γ 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.

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