Platinum(IV)-Gold(I) Agents with Promising Anticancer Activity: Selected Studies in 2D and 3D Triple-Negative Breast Cancer Models

New heterometallic binuclear and trinuclear platinum(IV)-gold(I) compounds of the type [Pt(L)nCl2(OH){(OOC-4-C6H4-PPh2)AuCl}x] (L=NH3, n=2; x=1, 2; L=diaminocyclohexane, DACH, n=1; x=2) are described. These compounds are cytotoxic and selective against a small panel of renal, bladder, ovarian, and breast cancer cell lines. We selected a trinuclear PtAu2 compound containing the PtIV core based on oxaliplatin, to further investigate its cell-death pathway, cell and organelle uptake and anticancer effects against the triple-negative breast cancer (TNBC) MDA-MB-231 cell line. This compound induces apoptosis and accumulates mainly in the nucleus and mitochondria. It also exerts remarkable antimigratory and antiangiogenic properties, and has a potent cytotoxic effect against TNBC 3D spheroids. Trinuclear compounds do not seem to display relevant interactions with calf thymus (CT) DNA and plasmid (pBR322) even in the presence of reducing agents, but inhibit pro-angiogenic enzyme thioredoxin reductase (TrxR) in TNBC cells. Two are better than one, heterometallic anticancer agents continue to impress: A Platinum(IV)-gold(I) agent inhibits several TNBC cancer hallmarks with no decreased drug sensitivity in 3D spheroids versus 2D cell culture models, inhibiting thioredoxin reductase (TrxR) in cells at concentrations five times lower than the IC50 value.image