Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs
Maria V. Babak, Kai Ren Chong, Peter Rapta, Μαρκέλλα Ζαννίκου, Hui Min Tang, Lisa Reichert, Meng Rui Chang, Владимир Кушнарев, Petra Heffeter, Samuel M. Meier, Zhi Chiaw Lim, Jian Yu Yap, Angela Casini, Irina V. Balyasnikova, Wee Han Ang
Abstract
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 Au III 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 Au III 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.