Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer,c haracterized by an aberrant metabolic phenotype with high metastatic capacity, resulting in poor patient prognoses and low survival rates.W e designed as eries of novel Au III cyclometalated prodrugs of energy-disrupting Type II antidiabetic drugs namely,m etformin 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.

Investigation of the Effects and Mechanisms of Anticancer Action of a Ru(II)‐Arene Iminophosphorane Compound in Triple Negative Breast Cancer Cells

“…We focused on examples of compounds that have been efficacious in vivo and their mechanisms studied (at least in a preliminary way). Some other relevant examples have been recently reported [10,11] …”

Development of immunoliposomes containing cytotoxic gold payloads against HER2-positive breast cancers

“…This may be explained by the high toxicity displayed by several gold(I) phosphane-containing compounds against triplenegative breast cancers. [47][48][49] To assess targeting selectivity, we tested Immunolipo-Tras-1 and Immunolipo-Tras-2, as well as their respective controls: gold compounds 1, 2, goldcontaining liposomes Lipo-1, Lipo-2, liposomes containing no drug (empty lipo), immunoliposomes containing no drug (empty immunolipo) and free mAb trastuzumab.…”

Water‐Soluble Gold(III)–Metformin Complex Alters Mitochondrial Bioenergetics in Breast Cancer Cells

“…In the course of submitting this manuscript, Ang et al. reported Au‐metformin and phenformin anticancer constructs [11] . We hypothesized that improved mitochondrial targeting of cationic organogold(III) complexes bearing metformin donor ligands would result in a novel class of compounds with significantly improved anticancer potential and mitochondrial targeting.…”