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A bismuth diethyldithiocarbamate compound induced apoptosis via mitochondria-dependent pathway and suppressed invasion in MCF-7 breast cancer cells

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Abstract

Interest in bismuth(III) dithiocarbamate complexes as potential drug candidates is increasing due to their low toxicity compared to other group 15 elements (pnictogen) of the periodic table. Bismuth dithiocarbamate compounds have been reported to induce greater cytotoxicity in various human carcinoma cancer cell lines. Using various in vitro cancer-related assays, we investigated the antiproliferative activity of bismuth diethyldithiocarbamate, denoted as 1, against the MCF-7 human breast adenocarcinoma cell line and the effect on genes that may be involved in antiproliferation, apoptosis, DNA fragmentation, invasion and polyubiquitination functions. In general, 1 exhibited high cytotoxicity in MCF-7 cells, with an IC50 of 1.26 ± 0.02 µM, by inducing the intrinsic apoptotic pathway, as ascertained by measurements of intracellular reactive oxygen species (ROS), caspase activity, the amount of cytochrome c released and the extent of DNA fragmentation and by staining assays that reveal apoptotic cells. In addition, 1 significantly attenuated cell invasion and modulated several cancer-related genes, including PLK2, FIGF, FLT4, PARP4, and HDAC11, as determined via gene expression analysis. The NF-κB signaling pathway was inhibited by 1 upon the activation of Lys48- and Lys63-linked polyubiquitination, thus leading to its degradation via the proteasome. Overall, 1 has the potential to act as an antiproliferative agent and a proteasome inhibitor in estrogen-positive breast cancer.

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Acknowledgements

The authors thanked Prof Edward R.T. Tiekink for providing the sample and Universiti Malaya for providing the grants under High Impact Research Schemes and collaborated with us by providing the compounds and the funding. The authors also thanked Prof Dr Noor Saadah Abd Rahman, the Deputy Vice Chancellor (Research and Innovation) at the University of Malaya for giving us the consent to publish the data.

Funding

This research was funded by Ministry of Higher Education, Malaysia, grant number UM.C/HIR-MOHE/SC/03 and UM.C/HIR-MOHE/SC/12.

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  1. Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia

    Pit Foong Chan, Kok Pian Ang & Roslida Abd Hamid

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Conceptualization, RAH; methodology, RAH; validation, CPF and RAH; formal analysis, CPF; investigation, CPF; data curation, CPF; writing—original draft preparation, CPF; writing—review and editing, RAH; visualization, CPF; supervision, RAH; project administration, RAH All authors have read and agreed to the published version of the manuscript.

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Correspondence to Roslida Abd Hamid.

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Chan, P.F., Ang, K.P. & Hamid, R.A. A bismuth diethyldithiocarbamate compound induced apoptosis via mitochondria-dependent pathway and suppressed invasion in MCF-7 breast cancer cells. Biometals 34, 365–391 (2021). https://doi.org/10.1007/s10534-021-00286-0

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