A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton

Abstract

The substitution inert platinum agent [Pt(1S,2Sdiaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] 2+ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.

Up-regulation of SPC25 promotes breast cancer

“…Furthermore, Kostrhunova et al . found that a subset of new platinum antitumor agents kills cells in part by altering microtubule cytoskeleton organization [18]. It is therefore possible that SPC25 might promote BC development and progression by binding to microtubule proteins.…”

Oxamusplatin: a cytotoxic Pt(ii) complex of a nitrogen mustard with resistance to thiol based sequestration displays enhanced selectivity towards cancer

“…Recently it was shown by Brabec et al that certain Pt(IV) complexes inhibit the organization of microtubule. 48 Here in, we find that oxamusplatin not only targets DNA but disrupts the organization of microtubules affecting the cytoskeleton.…”

Up-Regulation of VCAN Promotes the Proliferation, Invasion and Migration of HCC and Serves as a Biomarker

“…Some previous studies have shown that tubulin plays an important role in cell cycle and cell proliferation. Many antitumor drugs kill cancer cells by changing the microstructure of cancer cells (26,27). Therefore, in the development and progression of HCC, VCAN is likely to interact with the microtubule structure to promote cancer.…”