Journal
MOLECULES
Volume 21, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/molecules21081088
Keywords
di-2-pyridylhydrazone dithiocarbamate S-propionic acid; antiproliferative activity; apoptosis; autophagy; cell cycle arrest; antagonistic effect; copper complex; ROS-uncorrelated cytotoxicity; tumor microenvironment; antitumor mechanism
Funding
- Natural Science Foundation of China [21571153]
- Henan Science and Technology Agency [114300510012, 132102310250, 152300410118]
- Plan of Health Scientific and Technological Innovation Talents of Henan Province [2109901]
- Shaoshan Li and Graduate innovation project of Xinxiang Medical University [YJSCX201503Z]
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The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC50 = 1.3 +/- 0.3 mu M for HepG2, and 2.5 +/- 0.6 mu M for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20-30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA-Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA-Cu lacked this effect, which explained the difference in their antiproliferative activity.
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