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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Pyrrolidine Dithiocarbamate Enhances the Cytotoxic Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia Cells

Author(s): Simin Yu, Zhuowang Ge, Weixiang Chen and Jinbin Han*

Volume 26, Issue 11, 2023

Published on: 08 February, 2023

Page: [2067 - 2076] Pages: 10

DOI: 10.2174/1386207326666230123155944

Price: $65

Abstract

Background: More than 95% patients with acute promyelocytic leukemia (APL) carry the PML-RARα fusion oncoprotein. Arsenic trioxide (ATO) is an efficacious therapeutic agent for APL, and the mechanism involves the binding with PML and degradation of PML-RARα protein. Pyrrolidine dithiocarbamate (PDTC) demonstrates the function of facilitating the cytotoxic effect of ATO.

Purpose: To investigate whether PDTC is potential to enhance the cytotoxic effect of ATO to APL cells by acting on PML-RARα oncoproteins.

Methods: Inhibitory effects of drugs on cell viability were examined by CCK-8 test, and apoptosis was evaluated by flow cytometry. Western blotting and immunofluorescence assays were used to explore the mechanism.

Results: PDTC improved the effect of ATO on inhibiting proliferation of NB4 cells in vitro. Further, PDTC-ATO promoted apoptosis and cell cycle arrest in NB4 cells. The expression of caspase- 3 and Bcl-2 was reduced in PDTC-ATO-treated NB4 cells, while cleaved caspase-3 and Bax was up-regulated. Furthermore, less PML-RARα expression were found in PDTC-ATO-treated NB4 cells than that in NB4 cells treated with ATO singly. Laser confocal microscopy showed that protein colocalization of PML and RARα was disrupted more significantly by PDTC-ATO treatment than that with ATO monotherapy.

Conclusion: In conclusion, PDTC enhanced the cytotoxic effect of ATO on APL, and the mechanism was, at least in part, related to the promotion of ATO-induced degradation of PML-RARα fusion protein via forming a complex PDTC-ATO.

Keywords: Leukemia, dithiocarbamate, arsenic, PML-RARα, apoptosis, cytotoxic effect.

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