MIT scientists develop new platinum compound selective against cancer cells!!

[Lani]

New platinum compound shows promise in tumor cells
[MIT]
CAMBRIDGE, Mass. — MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.
The new compound, mitaplatin, combines cisplatin with another compound, dichloroacetate (DCA), which can alter the properties of mitochondria selectively in cancer cells. Cancer cells switch their mitochondrial properties to change the way they metabolize glucose compared to normal cells, and DCA specifically targets the altered mitochondria, leaving normal cells intact.
"This differential effect conveys on mitaplatin the ability to kill cancer cells selectively in a co-culture with normal fibroblast cells, the latter being unaffected at the doses that we apply," says Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry.
How they did it: The chemists designed mitaplatin so that when it enters a cell, it releases cisplatin and two units of DCA by intracellular reduction. Therefore, mitaplatin can attack nuclear DNA with cisplatin and mitochondria with DCA. DCA promotes the release of cell-death-promoting factors from the mitochondria, enhancing the cancer cell-killing abilities of cisplatin.
Next steps: Lippard's laboratory has shown that in rodents, mitaplatin can be tolerated at much higher doses than cisplatin, and they have begun studies in mice transplanted with human tissues. If those results are promising, the researchers plan more studies for further demonstration of mitaplatin's ability in cancer therapy.
EARLY VIEW: ABSTRACT: Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate
[Proceedings of the National Academy of Sciences]
The unique glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated 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(O2CHCl2)2Cl2], mitaplatin, in which two DCA units are appended to the axial positions of a six-coordinate Pt(IV) center. The negative intracellular redox potential reduces the platinum to release cisplatin, a Pt(II) compound, and two equivalents 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) compounds and is comparable to that of cisplatin. Mitaplatin alters the mitochondrial membrane potential gradient (Δ?m) of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction 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.