Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

被引:7
|
作者
Jiang, Dandan [1 ]
Ma, Peizhi [1 ]
机构
[1] Peoples Hosp Zhengzhou Univ, Henan Prov Peoples Hosp, Dept Pharm, Zhengzhou, Henan, Peoples R China
来源
FRONTIERS IN ONCOLOGY | 2022年 / 12卷
基金
中国国家自然科学基金;
关键词
gastric cancer; HDAC6; EMT; canagliflozin; enzyme inhibition; TARGET;
D O I
10.3389/fonc.2022.1057455
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to the lack of effective targeting drugs. The mechanisms of non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 is mostly located in the cytoplasm to deacetylate non-histone substrates, which has been identified as a critical promoter of many oncogenic pathways in cancers, including gastric cancer. Nevertheless, its inhibitor has not been applied in gastric cancer clinically. In this study, we identified canagliflozin as an active HDAC6-targeted inhibitor from FDA-approved Drug Library by enzymatic assay. The strong affinity of the compounds with HDAC6 was further verified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). In addition, molecular docking showed that canagliflozin could bind to the active pocket of HDAC6 and form interactions with key residues. Further experiments revealed that canagliflozin could effectively inhibit the migration and epithelial-mesenchymal-transition (EMT) of gastric cancer cells in vitro and in vivo. These results reveal a novel finding that canagliflozin has the potential to be an effective agent in inhibiting gastric cancer metastasis.
引用
收藏
页数:9
相关论文
共 50 条
  • [1] Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation
    Lin, Ching
    Hsu, Jui-Ling
    Hsu, Yu-Tung
    Fan, Kuo-Chen
    Wu, Sian-Siou
    Lin, Miao-Hsia
    Guh, Jih-Hwa
    Yu, Chao-Wu
    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2025, 40 (01)
  • [2] The Role of HDAC6 in Cancer
    Aldana-Masangkay, Grace I.
    Sakamoto, Kathleen M.
    JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY, 2011,
  • [3] HDAC6 and Ovarian Cancer
    Haakenson, Joshua
    Zhang, Xiaohong
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2013, 14 (05) : 9514 - 9535
  • [4] Novel Single Inhibitor of HDAC6/8 and Dual Inhibitor of PI3K/HDAC6 as Potential Alternative Treatments for Prostate Cancer
    Guerra, Fabiana Selos
    Rodrigues, Daniel Alencar
    Fraga, Carlos Alberto Manssour
    Fernandes, Patricia Dias
    PHARMACEUTICALS, 2021, 14 (05)
  • [5] Ricolinostat is not a highly selective HDAC6 inhibitor
    Guillaume Médard
    Jason M. Sheltzer
    Nature Cancer, 2023, 4 : 807 - 808
  • [6] Ricolinostat is not a highly selective HDAC6 inhibitor
    Medard, Guillaume
    Sheltzer, Jason M.
    NATURE CANCER, 2023, 4 (06) : 807 - 808
  • [7] Carbenoxolone disodium suppresses the migration of gastric cancer by targeting HDAC6
    Song, Zhiyu
    Zhao, Chenglong
    Yan, Jingjing
    Jiang, Dandan
    Jia, Gang
    FUTURE MEDICINAL CHEMISTRY, 2023, 15 (04) : 333 - 344
  • [8] Tau - an inhibitor of deacetylase HDAC6 function
    Perez, Mar
    Santa-Maria, Ismael
    Gomez de Barreda, Elena
    Zhu, Xiongwei
    Cuadros, Raquel
    Roman Cabrero, Jose
    Sanchez-Madrid, Francisco
    Dawson, Hana N.
    Vitek, Michael P.
    Perry, George
    Smith, Mark A.
    Avila, Jesus
    JOURNAL OF NEUROCHEMISTRY, 2009, 109 (06) : 1756 - 1766
  • [9] Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer
    Zeleke, Tizita Z.
    Pan, Qingfei
    Chiuzan, Codruta
    Onishi, Maika
    Li, Yuxin
    Tan, Haiyan
    Alvarez, Mariano J.
    Honan, Erin
    Yang, Min
    Chia, Pei Ling
    Mukhopadhyay, Partha
    Kelly, Sean
    Wu, Ruby
    Fenn, Kathleen
    Trivedi, Meghna S.
    Accordino, Melissa
    Crew, Katherine D.
    Hershman, Dawn L.
    Maurer, Matthew
    Jones, Simon
    High, Anthony
    Peng, Junmin
    Califano, Andrea
    Kalinsky, Kevin
    Yu, Jiyang
    Silva, Jose
    NATURE CANCER, 2023, 4 (02) : 257 - +
  • [10] Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer
    Tizita Z. Zeleke
    Qingfei Pan
    Codruta Chiuzan
    Maika Onishi
    Yuxin Li
    Haiyan Tan
    Mariano J. Alvarez
    Erin Honan
    Min Yang
    Pei Ling Chia
    Partha Mukhopadhyay
    Sean Kelly
    Ruby Wu
    Kathleen Fenn
    Meghna S. Trivedi
    Melissa Accordino
    Katherine D. Crew
    Dawn L. Hershman
    Matthew Maurer
    Simon Jones
    Anthony High
    Junmin Peng
    Andrea Califano
    Kevin Kalinsky
    Jiyang Yu
    Jose Silva
    Nature Cancer, 2023, 4 : 257 - 275