A Thiosemicarbazone Derivative Induces Triple Negative Breast Cancer Cell Apoptosis: Possible Role of MiRNA-125a-5p and MiRNA-181a-5p

Overview

Journal Genes Genomics

Specialty Genetics

Date 2019 Sep 22

PMID 31541355

Citations 10

Authors

Rania El Majzoub

Mohammad Fayyad-Kazan

Assaad Nasr El Dine

Rawan Makki

Eva Hamade

Rene Gree

Ali Hachem

Rabih Talhouk

Hussein Fayyad-Kazan

Bassam Badran

Affiliations

Soon will be listed here.

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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References

Willimott S, Wagner S . miR-125b and miR-155 contribute to BCL2 repression and proliferation in response to CD40 ligand (CD154) in human leukemic B-cells. J Biol Chem. 2011; 287(4):2608-17. PMC: 3268420. DOI: 10.1074/jbc.M111.285718. View

Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz C, Dantis L . Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996; 14(3):737-44. DOI: 10.1200/JCO.1996.14.3.737. View

Hu W, Feng Z, Levine A . The Regulation of Multiple p53 Stress Responses is Mediated through MDM2. Genes Cancer. 2012; 3(3-4):199-208. PMC: 3494373. DOI: 10.1177/1947601912454734. View

Iorio M, Ferracin M, Liu C, Veronese A, Spizzo R, Sabbioni S . MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005; 65(16):7065-70. DOI: 10.1158/0008-5472.CAN-05-1783. View

Chacon R, Costanzo M . Triple-negative breast cancer. Breast Cancer Res. 2010; 12 Suppl 2:S3. PMC: 2972557. DOI: 10.1186/bcr2574. View

Zhang B, Pan X, Cobb G, Anderson T . microRNAs as oncogenes and tumor suppressors. Dev Biol. 2006; 302(1):1-12. DOI: 10.1016/j.ydbio.2006.08.028. View

Chen G, Zhao Z, Zhou H, Liu Y, Yang H . Systematic analysis of microRNA involved in resistance of the MCF-7 human breast cancer cell to doxorubicin. Med Oncol. 2009; 27(2):406-15. DOI: 10.1007/s12032-009-9225-9. View

Mollereau B, Ma D . The p53 control of apoptosis and proliferation: lessons from Drosophila. Apoptosis. 2014; 19(10):1421-9. PMC: 4167030. DOI: 10.1007/s10495-014-1035-7. View

Leivonen S, Sahlberg K, Makela R, Due E, Kallioniemi O, Borresen-Dale A . High-throughput screens identify microRNAs essential for HER2 positive breast cancer cell growth. Mol Oncol. 2013; 8(1):93-104. PMC: 5528509. DOI: 10.1016/j.molonc.2013.10.001. View

10.

Carey L, Winer E, Viale G, Cameron D, Gianni L . Triple-negative breast cancer: disease entity or title of convenience?. Nat Rev Clin Oncol. 2010; 7(12):683-92. DOI: 10.1038/nrclinonc.2010.154. View

11.

Kumar M, Lu J, Mercer K, Golub T, Jacks T . Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007; 39(5):673-7. DOI: 10.1038/ng2003. View

12.

Rimawi M, Mayer I, Forero A, Nanda R, Goetz M, Rodriguez A . Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 2013; 31(14):1726-31. PMC: 3641695. DOI: 10.1200/JCO.2012.44.8027. View

13.

Cho W . OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer. 2007; 6:60. PMC: 2098778. DOI: 10.1186/1476-4598-6-60. View

14.

Kalinowski D, Richardson D . The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev. 2005; 57(4):547-83. DOI: 10.1124/pr.57.4.2. View

15.

Raisch J, Darfeuille-Michaud A, Nguyen H . Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol. 2013; 19(20):2985-96. PMC: 3662938. DOI: 10.3748/wjg.v19.i20.2985. View

16.

Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T . Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors. Clin Cancer Res. 2003; 9(11):4092-100. View

17.

Vandresen F, Falzirolli H, Almeida Batista S, da Silva-Giardini A, de Oliveira D, Catharino R . Novel R-(+)-limonene-based thiosemicarbazones and their antitumor activity against human tumor cell lines. Eur J Med Chem. 2014; 79:110-6. DOI: 10.1016/j.ejmech.2014.03.086. View

18.

Pena-Chilet M, Martinez M, Perez-Fidalgo J, Peiro-Chova L, Oltra S, Tormo E . MicroRNA profile in very young women with breast cancer. BMC Cancer. 2014; 14:529. PMC: 4223555. DOI: 10.1186/1471-2407-14-529. View

19.

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

20.

Westphal D, Dewson G, Czabotar P, Kluck R . Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta. 2011; 1813(4):521-31. DOI: 10.1016/j.bbamcr.2010.12.019. View