Copper complex derived from S-benzyldithiocarbazate and 3-acetylcoumarin induced apoptosis in breast cancer cell
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Copper complexes have been widely studied for the anti-tumour application as cancer cells are reported to take up greater amounts of copper than normal cells. Preliminary study revealed that the newly synthesised copper complex [Cu(SBCM)2] displayed marked anti-proliferative towards triple-negative MDA-MB-231 breast cancer cells. Therefore, Cu(SBCM)2 has great potential to be developed as an agent for the management of breast cancer. The present study was carried out to investigate the mode of cell death induced by Cu(SBCM)2 towards MDA-MB-231 breast cancer cells. The inhibitory and morphological changes of MDA-MB-231 cells treated with Cu(SBCM)2 was determined by using MTT assay and inverted light microscope, respectively. The safety profile of Cu(SBCM)2 was also evaluated towards human dermal fibroblast (HDF) normal cells. Confirmation of apoptosis and cell cycle arrest were determined by flow cytometry analysis. The expression of p53, Bax, Bcl-2 and MMP2 protein were detected with western blot analysis. Cu(SBCM)2 significantly inhibited the growth of MDA-MB-231 cells in a dose-dependent manner with GI50 18.7 ± 3.06 µM. Indeed, Cu(SBCM)2 was less toxic towards HDF normal cells with GI50 31.8 ± 4.0 µM. Morphological study revealed that Cu(SBCM)2-treated MDA-MB-231 cells experienced cellular shrinkage, membrane blebbing, chromatin condensation and formation of apoptotic bodies, suggesting that Cu(SBCM)2 induced apoptosis in the cells, which was confirmed by Annexin-V/PI flow cytometry analysis. It was also found that Cu(SBCM)2 induced G2/M phase cell cycle arrest towards MDA-MB-231 cells. The induction of apoptosis and cell cycle arrest in the present study is possibly due to the down-regulation of the mutant p53 and MMP2 protein. In conclusion, Cu(SBCM)2 can be developed as a targeted therapy for the treatment of triple-negative breast cancer.
KeywordsCopper(II) Schiff-base Breast cancer Apoptosis Cell cycle arrest p53
The present work was financially supported by MAHSA Research Grant RP89-02/16 and conducted in Universiti Putra Malaysia. Special thanks are delivered to staff members of the Laboratory of Vaccine and Immunotherapeutics from Universiti Putra Malaysia for their support and assistance in completing this study.
JBF, YST, CWH and LSY contributed to the design of the study and interpretation of data. LSY allowed us to use laboratory facilities for present study. MLL synthesised and characterized the copper complex. For data acquisition, JBF, JHL and YZL contributed to the MTT assay, Morphological study and p53 Western blot analysis. JBF, RZA, VED, NAR, CYB, LCC contributed to Flow cytometry (Cell cycle and apoptosis assay) and Western blot analysis. This manuscript is prepared and critically revised by JBF, YST, CWH and LSY.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Abdullah NA, Wan Mahiyuddin WR, Muhammad NA, Ali ZM, Ibrahim L, Ibrahim Tamim NS, Mustafa AN, Kamaluddin MA (2013) Survival rate of breast cancer patients in Malaysia: a population-based study. Asian Pac J Cancer Prev 14(8):4591–4594. https://doi.org/10.7314/APJCP.2013.14.8.4591 CrossRefPubMedGoogle Scholar
- Bagihalli GB, Avaji PG, Patil SA, Badami PS (2008) Synthesis, spectral characterization, in vitro antibacterial, antifungal and cytotoxic activities of Co(II), Ni(II) and Cu(II) complexes with 1,2,4-triazole Schiff bases. Eur J Med Chem 43:2639–2649. https://doi.org/10.1016/j.ejmech.2008.02.013 CrossRefPubMedGoogle Scholar
- Barve V, Ahmed F, Adsule S, Banerjee S, Kulkarni S, Katiyar P, Anson CE, Powell AK, Padhye S, Sarkar FH (2006) Synthesis, molecular characterization, and biological activity of novel synthetic derivatives of chromen-4-one in human cancer cells. J Med Chem 49:3800–3808. https://doi.org/10.1021/jm051068y CrossRefPubMedGoogle Scholar
- Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, Lamantia G, Colombo N, Cortinovis S, Dessanai MA, Nolè F, Veglia F, Cipolla CM (2010) Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 28:3910–3916. https://doi.org/10.1200/JCO.2009.27.3615 CrossRefPubMedGoogle Scholar
- Datta P, Mukhopadhyay AP, Manna P, Tiekink ER, Sil PC, Sinha C (2011) Structure, photophysics, electrochemistry, DFT calculation, and in vitro antioxidant activity of coumarin Schiff base complexes of Group 6 metal carbonyls. J Inorg Biochem 105:577–588. https://doi.org/10.1016/j.jinorgbio.2010.04.013 CrossRefPubMedGoogle Scholar
- Foo JB, Saiful Yazan L, Tor YS, Wibowo A, Ismail N, Armania N, Cheah YK, Abdullah R (2016) Dillenia suffruticosa dichloromethane root extract induced apoptosis towards MDA-MB-231 triple-negative breast cancer cells. J Ethnopharmacol 187:195–204. https://doi.org/10.1016/j.jep.2016.04.048 CrossRefPubMedGoogle Scholar
- GLOBOCAN (2012) Breast cancer: estimated incidence, mortality and prevalence world wide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 10 March 2018
- Kulkarni A, Patil SA, Badami PS (2009) Synthesis, characterization, DNA cleavage and in vitro antimicrobial studies of La(III), Th(IV) and VO(IV) complexes with Schiff bases of coumarin derivatives. Eur J Med Chem 44:2904–2912. https://doi.org/10.1016/j.ejmech.2008.12.012 CrossRefPubMedGoogle Scholar
- Low M, Paulus G, Dorlet P, Guillot R, Rosli R, Delsuc N, Crouse K, Policar C (2015) Synthesis, characterization and biological activity of Cu(II), Zn(II) and Re(I) complexes derived from S-benzyldithiocarbazate and 3-acetylcoumarin. Biometals 28(3):553–566. https://doi.org/10.1007/s10534-015-9831-2 CrossRefPubMedGoogle Scholar
- Padhye S, Yang H, Jamadar A, Cui Q, Chavan D, Dominiak K, McKinney J, Banerjee S, Dou QP, Sarkar F (2009) New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm Res 26:1874–1880. https://doi.org/10.1007/s11095-009-9900-8 CrossRefPubMedPubMedCentralGoogle Scholar
- Pearcey R, Brundage M, Drouin P, Jeffery J, Johnston D, Lukka H, MacLean G, Souhami L, Stuart G, Tu D (2002) Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20:966–972. https://doi.org/10.1200/JCO.2002.20.4.966 CrossRefPubMedGoogle Scholar