Abstract
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.
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Acknowledgements
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.
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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.
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Foo, J.B., Low, M.L., Lim, J.H. et al. Copper complex derived from S-benzyldithiocarbazate and 3-acetylcoumarin induced apoptosis in breast cancer cell. Biometals 31, 505–515 (2018). https://doi.org/10.1007/s10534-018-0096-4
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DOI: https://doi.org/10.1007/s10534-018-0096-4