Tumor resistance to
chemotherapy is the major obstacle to employ
cisplatin, one of the broadly used chemotherapeutic drugs, for effective treatment of various
tumors in the clinic. Most acknowledged mechanisms of
cancer resistance to
cisplatin focus on increased nuclear DNA repair or detoxicity of
cisplatin. We previously demonstrated that there was a unique metabolic profile in
cisplatin-resistant (CP-r) human epidermoid
adenocarcinoma KB-CP 20 and
hepatoma BEL 7404-CP 20
cancer cells. In this study, we further defined hyperpolarized mitochondrial membrane potentials (Δψ(m)) in CP-r KB-CP 20 and BEL 7404-CP 20 cells compared to the
cisplatin-sensitive (CP-s) KB-3-1 and BEL 7404 cells. Based on the
mitochondrial dysfunction,
mitaplatin was designed with two mitochondrial-targeting moieties [dichloroacetate (DCA) units] to the axial positions of a six-coordinate Pt(IV) center to sensitize
cisplatin resistance. It was found that
mitaplatin induced more apoptosis in CP-r KB-CP 20 and BEL 7404-CP 20 cells than that of
cisplatin, DCA and
cisplatin/DCA compared on an equal molar basis. There was more
platinum accumulation in
mitaplatin-treated CP-r cells due to enhanced transmembrane permeability of lipophilicity, and
mitaplatin also showed special targeting to mitochondria. Moreover, in the case of treatment with
mitaplatin, the dramatic collapse of Δψ(m) was shown in a dose-dependent manner, which was confirmed by FACS and confocal microscopic measurements. Reduced
glucose utilization of CP-r cells was detected with specifically inhibited phosphorylation of
pyruvate dehydrogenase (PDH) at Ser-232, Ser-293, and Ser-300 of the E1α subunit when treated with
mitaplatin, which was indicated to modulate the abnormal glycolysis of resistant cells. The present study suggested novel mitochondrial mechanism of
mitaplatin circumventing
cisplatin resistance toward CP-r cells as a carrier across membrane to produce CP-like cytotoxicity and DCA-like mitochondria-dependent apoptosis. Therefore, mitochondria targeting compounds would be more vulnerable and selective to overcome
cisplatin resistance due to the unique metabolic properties of CP-r
cancer cells.