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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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-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.

Details

Title
MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells
Author
Chen, Mei-Chuan 1 ; Yu-Chen, Lin 2 ; Liao, Yu-Hsuan 3 ; Jing-Ping Liou 4 ; Chun-Han, Chen 5   VIAFID ORCID Logo 

 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan; [email protected] (M.-C.C.); [email protected] (Y.-H.L.); Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 110, Taiwan 
 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; [email protected] 
 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan; [email protected] (M.-C.C.); [email protected] (Y.-H.L.) 
 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan; [email protected] 
 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; [email protected]; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan 
First page
1617
Publication year
2019
Publication date
2019
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2547537776
Copyright
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.