Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate
Abstract
The unique glycolytic metab. of most solid tumors, known as the Warburg effect, is assocd. with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. Here, we present the synthesis, characterization, and anticancer properties of c,t,c-[Pt(NH3)2(02CHCl2)2Cl2], mitaplatin, in which two DCA units are appended to the axial positions of a six-coordinate Pt(IV) center. The neg. intracellular redox potential reduces the platinum to release cisplatin, a Pt(II) compd., and two equiv. of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt(IV) compds. and is comparable to that of cisplatin. Mitaplatin alters the mitochondrial membrane potential gradient (Δψm) of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular redn. of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance. [on SciFinder(R)]