ABSTRACT
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates. We designed a series of novel AuIII cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely, metformin and phenformin. Prodrug activation and release of the metformin ligand was achieved by tuning the cyclometalated AuIII fragment. The lead complex 3met was 6000-fold more cytotoxic compared to uncoordinated metformin and significantly reduced tumor burden in mice with aggressive breast cancers with lymphocytic infiltration into tumor tissues. These effects was ascribed to 3met interfering with energy production in TNBCs and inhibiting associated pro-survival responses to induce deadly metabolic catastrophe.
Subject(s)
Antineoplastic Agents/metabolism , Metformin/metabolism , Prodrugs/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Autophagy/drug effects , Cell Line, Tumor , Coordination Complexes/chemistry , Drug Evaluation, Preclinical , Energy Metabolism/drug effects , Gold/chemistry , Humans , Metformin/chemistry , Mice , Molecular Conformation , Phenformin/chemistry , Phenformin/metabolism , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/therapeutic use , Transplantation, Heterologous , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
Fluorescence microscopy has emerged as an attractive technique for imaging intracellular Pt species arising from exposure to clinical anticancer drugs such as cisplatin. A rhodamine-B based fluorogenic probe termed Rho-DDTC can be activated selectively in the presence of Pt(II) compounds, and possesses the ability to discriminate Pt(II) species from Pt(IV) carboxylate prodrug complexes, thereby providing a unique platform to investigate the reduction of these Pt(IV) complexes after cell entry. In this report, we seek to establish the mechanism of activation of Rho-DDTC through a structure-activity relationship study on its structural analogues.
