Journal
FRONTIERS IN PHARMACOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.626065
Keywords
antiproliferative activities; drug resistance; histone deacetylase (HDAC) inhibitor; N-hydroxyacrylamide; β -carboline
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Funding
- Applied Research Projects of Nantong City [JC2018125, JC2019145, MS12020047]
- Doctoral Scientific Research Foundation of Affiliated Hospital of Nantong University [Tdb19013]
- Priority Academic Programs Development of Jiangsu Higher Education Institutions (PAPD)
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The novel hybrid CHC showed high antiproliferative effects on drug-sensitive and drug-resistant cells, selectively inhibited HDAC1/6, and exhibited strong inhibitory potency to drug-resistant hepatic tumors in mice.
A novel hybrid CHC was designed and synthesized by conjugating beta-carboline with an important active fragment N-hydroxyacrylamide of histone deacetylase (HDAC) inhibitor by an amide linkage to enhance antitumor efficacy/potency or even block drug resistance. CHC displayed high antiproliferative effects against drug-sensitive SUMM-7721, Bel7402, Huh7, and HCT116 cells and drug-resistant Bel7402/5FU cells with IC50 values ranging from 1.84 to 3.27 mu M, which were two-to four-fold lower than those of FDA-approved HDAC inhibitor SAHA. However, CHC had relatively weak effect on non-tumor hepatic LO2 cells. Furthermore, CHC exhibited selective HDAC1/6 inhibitory effects and simultaneously augmented the acetylated histone H3/H4 and alpha-tubulin, which may make a great contribution to their antiproliferative effects. In addition, CHC also electrostatically interacted with CT-DNA, exerted remarkable cellular apoptosis by regulating the expression of apoptosis-related proteins and DNA damage proteins in Bel7402/5FU cells, and significantly accumulated cancer cells at the G2/M phase of the cell cycle by suppressing CDK1 and cyclin B protein with greater potency than SAHA-treated groups. Finally, CHC displayed strong inhibitory potency to drug-resistant hepatic tumors in mice. Our designed and synthetic hybrid CHC could be further developed as a significant and selective anticancer agent to potentially treat drug-resistant hepatocellular carcinoma.
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