Abstract
Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic agents, however, patients developed resistance to these clinical agents after initial therapeutic treatments. Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms, and targets for overcoming drug resistance. In this study, we have identified a panel of cobalt complexes that were able to specifically induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells. Consistently, our reported anti-cancer functions of cobalt complexes 1–6 towards multidrug-resistant cancers have suggested the protective and non-toxic properties of cobalt metal-ions based compounds in anti-cancer therapies. As demonstrated in xenograft mouse model, our results also confirmed the identified cobalt complex 2 was able to suppress tumor growth in vivo. The anti-cancer effect of the cobalt complex 2 was further demonstrated to be exerted via the induction of autophagy, cell cycle arrest, and inhibition of cell invasion and P-glycoprotein (P-gp) activity. These data have provided alternative metal ion compounds for targeting drug resistance cancers in chemotherapies.
Highlights
Transition metal ions are essential for the proper functions of organisms; examples including copper, iron, and manganese ions work with proteins and enzymes for multiple biological processes such as electron transfer and catalysis
We have identified a panel of cobalt complexes that were able to induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells
Platinum complexes can work as effective anti-cancer agents via the induction of tumor cell death, cisplatin might lead to toxicity of neural or renal cells, as well as bone marrow-suppression
Summary
Transition metal ions are essential for the proper functions of organisms; examples including copper, iron, and manganese ions work with proteins and enzymes for multiple biological processes such as electron transfer and catalysis. Enriched copper ions found in cancer tissues are suggested to promote the angiogenesis processes in tumors. The use of copper ion-binding ligands is anticipated to provide a novel anti-cancer therapy [1]. Cisplatin (cis-[PtII(NH3)2Cl2]) can bind to the purine bases of DNA, thereby led to DNA damage resulting in apoptosis in cancer cells. Other transition metal complexes including zinc(II), copper(II), gold(III), copper chelating agents, and nonplatinum metal complexes such as ruthenium-containing compounds were studied for their potential as anti-cancer agents [1, 3,4,5,6,7]
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