title: Mitaplatin increases sensitivity of tumor cells to cisplatin by inducing mitochondrial dysfunction.
abstract: 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.
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xue
authors.forename: Song
authors.initials: S
authors.lastname: You
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Guo-Zhang
authors.initials: GZ
authors.lastname: Zou
authors.forename: Paul C
authors.initials: PC
authors.lastname: Wang
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhang
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D062845:Chloroacetates; D002945:Cisplatin / Q000494:pharmacology*; D003999:Dichloroacetic Acid / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D062845:Chloroacetates; D009944:Organoplatinum Compounds; C547058:mitaplatin; D003999:Dichloroacetic Acid; D002945:Cisplatin