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

The substitution
inert platinum agent [Pt­(1S,2S-diaminocyclohexane)­(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.