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A thiosemicarbazone derivative induces triple negative breast cancer cell apoptosis: possible role of miRNA-125a-5p and miRNA-181a-5p

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Abstract

Background

Breast cancer, the most commonly diagnosed malignancy in women, accounts for the highest cancer-related deaths worldwide. Triple negative breast cancer (TNBC), lacking the expression of estrogen, progesterone and HER2 receptors, has an aggressive clinical phenotype and is susceptible to chemotherapy but not to hormonal or targeted immunotherapy. In an attempt to identify potent and selective anti-TNBC agents, a set of thiosemicarbazone derivatives were screened for their cytotoxic activity against MDA-MB 231 breast cancer cell line.

Methods

MTT assay was used to examine cell viability. P53 phosphorylation status, poly (ADP-ribose) polymerase (PARP) cleavage as well as Bcl2 and Bax protein levels were assessed by Western blot. Quantitative Real Time-PCR was carried out to characterize miRNAs expression levels.

Results

Combining Cisplatin + thiosemicarbazone compound 4 showed potent anti-TNBC potential. Cisplatin + compound 4 significantly enhanced p53 phosphorylation, induced Bax amount, reduced Bcl2 protein levels, enhanced PARP cleavage and modulated miRNAs expression profile in TNBCs, with a particular overexpression of miR-125a-5p and miR-181a-5p. Intriguingly, miR-125a-5p and miR-181a-5p could significantly downregulate BCL2 expression by binding to their target sites in the 3′UTR.

Conclusions

Collectively, our results demonstrate an anti-TNBC activity of Cisplatin + thiosemicarbazone compound 4 combination mediated via induction of apoptosis.

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Acknowledgements

All participants are acknowledged in the authorship.

Funding

This work is supported by the Lebanese University and the Lebanese National Council for Scientific Research (CNRS-L). Financial support by the “Ligue contre le Cancer, Conseil Interrégional Grand Ouest” is also gratefully acknowledged.

Author information

Author notes

  1. Rania El Majzoub and Mohammad Fayyad-kazan contributed equally to this work.

  2. Hussein Fayyad-Kazan and Bassam Badran Joint senior co-authors.

Authors and Affiliations

  1. Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon

    Rania El Majzoub, Mohammad Fayyad-kazan, Rawan Makki, Eva Hamade, Hussein Fayyad-Kazan & Bassam Badran

  2. Laboratory for Medicinal Chemistry and Natural Products, Faculty of Sciences-I and PRASE-EDST, Lebanese University, Hadath, Beirut, Lebanon

    Assaad Nasr El Dine & Ali Hachem

  3. University Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, 35000, Rennes, France

    René Grée

  4. Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon

    Rabih Talhouk

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  1. Rania El Majzoub
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Correspondence to Bassam Badran.

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Conflict of interest

Rania El Majzoub, Mohammad Fayyad-kazan, Assaad Nasr El Dine, Rawan Makki, Eva Hamade, René Grée, Ali Hachem, Rabih Talhouk, Hussein Fayyad-Kazan and Bassam Badran declare that they have no conflict of interest.

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El Majzoub, R., Fayyad-kazan, M., Nasr El Dine, A. et al. A thiosemicarbazone derivative induces triple negative breast cancer cell apoptosis: possible role of miRNA-125a-5p and miRNA-181a-5p. Genes Genom 41, 1431–1443 (2019). https://doi.org/10.1007/s13258-019-00866-y

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  • DOI: https://doi.org/10.1007/s13258-019-00866-y

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