New platinum compound in treating tumour cells
1.A new compound named, mitaplatin, combines the cisplatin with an another compound, dichloroacetate (DCA), which alters the properties of the mitochondriaselectively in the cancer cells. Cancer cells switch to their mitochondrial properties to change the way they metabolize the glucose compared to that of the normal cells, and DCA specifically targets altered mitochondria, leaving the normal cells intact.(1)
2.This differential effect conveyed on mitaplatin the ability to kill cancer cell selectively in a co-culture with the normal fibroblast cells, the latter being unaffected at doses that we apply,". (1)
3.In rodents, mitaplatin can be tolerated at higher doses than cisplatin.the chemists designed mitaplatin such that when it enters a cell, it releases cisplatin and 2 units of DCA by intracellular reduction process. hence mitaplatin can attack the nuclear DNA with cisplatin and mitochondria with the DCA. DCA promotes release of cell-death-promoting factors from mitochondria, enhancing the cancer cell-killing abilities of the cisplatin. (1)
4.The negative intracellular redox potential will reduce the platinum to release cisplatin, which is a Pt(II) compound, and 2 equivalents of DCA. By a unique mechanism of action, mitaplatin will attack both nuclear DNA with the cisplatin and mitochondria with DCA selectively in cancer cells. (1)
5.The cytotoxicity of mitaplatin in variety of cancer cell lines equals to or exceeds that of all known Pt(IV) compounds and is comparable to cisplatin. (1)
6.Mitaplatin will alter the mitochondrial membrane potential gradient (Dpsm) of the cancer cells, and promotes the apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from the mitochondria to the nucleus. 7.Cisplatin formed upon the cellular reduction of mitaplatin enters nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as anticancer drug. (1)
Selective Killing of Cancer Cells by Mitaplatin.
1.One of the main obstacle to the cancer therapy is inability to successfully target the cancer cells, without harming normal cells. Although therapeutic agents are delivered locally to the primary tumor, systemic toxicities still arises.
2.Modern medicine needs desperately anti-cancer molecules that kill cancer cells and leave healthy cells unaffected. DCA has the selective toxicity toward the cancer cells by targeting PDK, then investigated whether mitaplatin would also display specificity for cancer. (2)
3.Therefore a coculture of normal fibroblasts and cancerous NTera-2 cells are treated with mitaplatin, cisplatin, or a mixture of one equivalent of cisplatin and two equivalents of DCA, the stoichiometric composition released upon intracellular mitaplatin reduction. (2)
4.In the coculture, cisplatin and the mixture of cisplatin and DCA killed both the fibroblasts and NTera-2 cancer cells, whereas mitaplatin selectively killed the cancer cells.The results that are obtained in this study provides a ompelling evidence that mitaplatin can selectively kill the cancer cells, leaving normal cells unaffected. (2)
Chemical structures and the mechanism of action of mitaplatin . After crossing plasma membrane, mitaplatin will be reduced to release of active drugs cisplatin and DCA. DCA will inhibit the mitochondrial PDK, which leads to the PDH activation and elevated glucose oxidation by promoting the influx of acetyl-CoA into mitochondria.DCA will decrease the mitochondrial membrane potential (Dps). Opening of Dps-sensitive mitochondrial transition pores
(MTPs) will lead to efflux of cyt c and AIF. Cisplatin formed in reduction
process interacts with its key target, i.e.,nuclear DNA.(3)
(ACCESSED ON oct 31st,2011,10:31a.m)
(ACCESSED ON oct 31st,2011,10:31a.m)
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