کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1316428 1499431 2016 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt(IV) derivative of oxaliplatin
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی معدنی
پیش نمایش صفحه اول مقاله
Potentiation of mitochondrial dysfunction in tumor cells by conjugates of metabolic modulator dichloroacetate with a Pt(IV) derivative of oxaliplatin
چکیده انگلیسی


• Pt(IV) derivatives of oxaliplatin conjugated with dichloroacetate were synthesized.
• Conjugates display markedly enhanced activity in cisplatin resistant tumor cells.
• DCA released in cancer cells affects mitochondria and metabolism of glucose.
• Conjugates activate an autophagic response in cancer cells.
• Toxicity of the conjugates in cancer cells can be potentiated by 5-fluorouracil.

The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin; (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA; (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose; (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells; (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic.

New anticancer prodrugs, Pt(IV) derivatives of oxaliplatin with dichloroacetate ligand(s) were synthesized. These conjugates display markedly enhanced activity in cisplatin sensitive- and resistant tumor cells. Mechanism of action of these prodrugs is connected with the effects on mitochondria, metabolism of glucose and autophagy is implicated.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Inorganic Biochemistry - Volume 156, March 2016, Pages 89–97
نویسندگان
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