The conjunction of the escalating global cancer incidence and the resistance towards chemotherapeutic agents has underscored the urgency for the development of novel therapeutics (1,2). The in vitro cytotoxicity of binuclear metal-centred complexes with bridging dicarboxylate and chelating 1,10-phenanthroline ligands has been well demonstrated. An array of studies, both in vitro and in vivo have delineated the variety of regulated cell death mechanisms stimulated by these complexes, and their differential action contingent upon the metal centre within the complex (3–6). This current research aims to elucidate the mechanism of action of a series of novel Cu(II), Mn(II) and Ag(I) complexes incorporating 1,10-phenanthroline ligands, in addition to ascertaining their therapeutic potential. Employing breast cancer (MCF-7) and normal human keratinocyte (HaCaT) cells, the cytotoxic capacity of these complexes has been established; in tandem with their precursors and the clinical therapeutic drug Cisplatin. Coupled with flow cytometric analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), the ability of these novel agents to induce the apoptotic pathway and the specific genes they stimulate has been elucidated.
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209–49.
2. Ota A, Tajima M, Mori K, Sugiyama E, Sato VH, Sato H. The selective cytotoxicity of silver thiosulfate, a silver complex, on MCF-7 breast cancer cells through ROS-induced cell death. Pharmacological Reports. 2021 Jun 1;73(3):847–57.
3. Kellett A, O’Connor M, McCann M, Howe O, Casey A, McCarron P, et al. Water-soluble bis(1,10-phenanthroline) octanedioate Cu 2+ and Mn 2+ complexes with unprecedented nano and picomolar in vitro cytotoxicity: Promising leads for chemotherapeutic drug development. Medchemcomm. 2011 Jul;2(7):579–84.
4. Thornton L, Dixit V, Assad LON, Ribeiro TP, Queiroz DD, Kellett A, et al. Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10-phenanthroline ligands: Antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity. J Inorg Biochem. 2016 Jun 1;159:120–32.
5. Rochford G, Molphy Z, Kavanagh K, McCann M, Devereux M, Kellett A, et al. Cu(ii) phenanthroline-phenazine complexes dysregulate mitochondrial function and stimulate apoptosis. Metallomics. 2020 Jan 1;12(1):65–78.
6. Slator C, Molphy Z, McKee V, Kellett A. Triggering autophagic cell death with a di-manganese(II) developmental therapeutic. Redox Biol. 2017 Aug 1;12:150–61.
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