Oxaliplatin derived monofunctional triazole-containing platinum(II) complex counteracts oxaliplatin-induced drug resistance in colorectal cancer.

ABSTRACT

Oxaliplatin-based chemotherapy is the current standard of care in adjuvant therapy for advanced colorectal cancer (CRC). But acquired resistance to oxaliplatin eventually occurs and becoming a major cause of treatment failure. Thus, there is an unmet need for developing new chemical entities (NCE) as new therapeutic candidates to target chemotherapy-resistant CRC. Novel Pt(II) complexes were designed and synthesized as cationic monofunctional oxaliplatin derivatives for DNA platination-mediated tumor targeting. The complex Ph-glu-Oxa sharing the same chelating ligand of diaminocyclohexane (DACH) with oxaliplatin but is equally potent in inhibiting the proliferation of HT29 colon cancer cells and its oxaliplatin-resistant phenotype of HT29/Oxa. The in vivo therapeutic potential of Ph-glu-Oxa was confirmed in oxaliplatin-resistant xenograft model demonstrating the reversibility of the drug resistance by the new complex and the efficacy was associated with the unimpaired high intracellular drug accumulation in HT29/Oxa. Guanosine-5'-monophosphate (5'-GMP) reactivity, double-strand plasmid DNA cleavage, DNA-intercalated ethidium bromide (EB) fluorescence quenching and atomic force microscopy (AFM)-mediated DNA denaturing studies revealed that Ph-glu-Oxa was intrinsically active as DNA-targeting agent. The diminished susceptibility of the complex to glutathione (GSH)-mediated detoxification, which confers high intracellular accumulation of the drug molecule may play a key role in maintaining cytotoxicity and counteracting oxaliplatin drug resistance.