Discovery of thiosemicarbazone-containing compounds with potent anti-proliferation activity against drug-resistant K562/A02 cells

https://doi.org/10.1016/j.bmcl.2020.127638Get rights and content

Highlights

  • Thiosemicarbazone-containing compounds were prepared as novel anti-leukemia agents.

  • 7e showed potent anti-leukemia effect on P-gp overexpressing drug resistant K562/A02 cells.

  • 7e could increase ROS levels in K562/A02 cells, thus inducing a collateral sensitivity effect.

  • 7e could regulate apoptosis-related proteins expression in drug resistant K562/A02 cells.

  • 7e displayed potent inhibitory effect on HDAC1/6 activity in drug resistant K562/A02 cells.

Abstract

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle to successful chemotherapy for leukemia. In this study, a series of thiosemicarbazone-containing compounds (4a-b, 7a-q) were synthesized. Biological evaluation showed that the most active compound 7e displayed potent anti-leukemia activity against P-gp overexpressing drug-resistant K562/A02 cells, with an IC50 value of 0.44 μM. Notably, compound 7e exhibited a selective killing effect on K562/A02 cells by dose-dependently increasing the intracellular levels of reactive oxygen species (ROS), thus exerting a potential collateral sensitivity (CS)-promoting effect in vitro. Moreover, compound 7e could inhibit HDAC1 and HDAC6, and induce the apoptosis of K562/A02 cells by increasing the expression of Bax, decreasing Bcl-2 protein level, and promoting the cleavage of caspase-3 and PARP, respectively. Overall, 7e may be a potential anti-cancer agent against drug-resistant myelogenous leukemia.

Graphical abstract

Compound 7e could more potently inhibit the proliferation of P-gp overexpressing K562/A02 cells than HDACs inhibitor SAHA.

  1. Download : Download high-res image (170KB)
  2. Download : Download full-size image

Section snippets

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the grants from the Natural Science Foundation of Jiangsu province (No. BK20171179 and BK20181151), the Six Talent Peaks Project in Jiangsu Province (Grant No. 2017-YY-039), Jiangsu Provincial 333 High-level Talents Cultivation Project (BRA201927), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. KYCX20_2506) and Jiangsu Training Programs of Innovation and Entrepreneurship for Undergraduates (Grant No. 201810313083X). We thank to Public

References (27)

Cited by (7)

View all citing articles on Scopus
1

These two authors contributed equally to this work.

View full text