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.