The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

Autor: Chung-Pu Wu, Sung-Han Hsiao, Suresh V. Ambudkar, Tai-Ho Hung, Sabrina Lusvarghi, Jyun-Cheng Wang, Yang-Hui Huang
Jazyk: angličtina
Rok vydání: 2019
Předmět:
ATP Binding Cassette Transporter
Subfamily B
Abcg2
medicine.drug_class
Cell Survival
Antineoplastic Agents
Apoptosis
P-glycoprotein
Catalysis
Article
Inorganic Chemistry
lcsh:Chemistry
medicine
ATP Binding Cassette Transporter
Subfamily G
Member 2
Humans
modulators
Molecular Targeted Therapy
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
histone deacetylase inhibitor
Spectroscopy
Oxadiazoles
biology
Organic Chemistry
Histone deacetylase inhibitor
Cancer
chemoresistance
General Medicine
medicine.disease
Drug Resistance
Multiple
Computer Science Applications
Neoplasm Proteins
TMP195
Multiple drug resistance
Histone Deacetylase Inhibitors
Molecular Docking Simulation
Drug repositioning
HEK293 Cells
lcsh:Biology (General)
lcsh:QD1-999
Drug Resistance
Neoplasm
breast cancer resistance protein
Cancer cell
Benzamides
Cancer research
biology.protein
Histone deacetylase
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 1
International Journal of Molecular Sciences, Vol 21, Iss 1, p 238 (2019)
ISSN: 1422-0067
DOI: 10.3390/ijms21010238
Popis: Multidrug resistance caused by the overexpression of the ATP-binding cassette (ABC) proteins in cancer cells remains one of the most difficult challenges faced by drug developers and clinical scientists. The emergence of multidrug-resistant cancers has driven efforts from researchers to develop innovative strategies to improve therapeutic outcomes. Based on the drug repurposing approach, we discovered an additional action of TMP195, a potent and selective inhibitor of class IIa histone deacetylase. We reveal that in vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs. We demonstrate that TMP195 inhibits the drug transport function, but not the protein expression of ABCB1 and ABCG2. The interaction between TMP195 with these transporters was supported by the TMP195-stimulated ATPase activity of ABCB1 and ABCG2, and by in silico docking analysis of TMP195 binding to the substrate-binding pocket of these transporters. Furthermore, we did not find clear evidence of TMP195 resistance conferred by ABCB1 or ABCG2, suggesting that these transporters are unlikely to play a significant role in the development of resistance to TMP195 in cancer patients.
Databáze: OpenAIRE
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