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

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127638. doi: 10.1016/j.bmcl.2020.127638. Epub 2020 Oct 22.

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.

Keywords: Collateral sensitivity; HDACs inhibitor; Multidrug resistance; P-glycoprotein; Thiosemicarbazones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Humans
  • K562 Cells
  • Leukemia / drug therapy*
  • Leukemia / metabolism
  • Reactive Oxygen Species / metabolism
  • Thiosemicarbazones / chemistry*
  • Thiosemicarbazones / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Thiosemicarbazones