Serum-Stable Gold(III) Bisphosphine Complex Induces Mild Mitochondrial Uncoupling and In Vivo Antitumor Potency in Triple Negative Breast Cancer
Adedamola S. Arojojoye, Chibuzor Olelewe, Sailajah Gukathasan, Jong H. Kim, Hemendra J. Vekaria, Sean Parkin, Patrick G. Sullivan, Samuel G. Awuah
Abstract
The preparation of cyclometalated complexes offers a path to stable materials, catalysts, and therapeutic agents. Here, we explore the anticancer potential of novel biphenyl organogold(III) cationic complexes supported by diverse bisphosphine ligands, Au-1–Au-5, toward aggressive glioblastoma and triple negative breast cancer cells (TNBCs). The [C^C] gold(III) complex, Au-3, exhibits significant tumor growth inhibition in a metastatic TNBC mouse model. Remarkably, Au-3 displays promising blood serum stability over a relevant therapeutic window of 24 h and alteration in the presence of excess L -GSH. The mechanism-of-action studies show that Au-3 induces mitochondrial uncoupling, membrane depolarization, and G1 cell cycle arrest and prompts apoptosis. To the best of our knowledge, Au-3 is the first biphenyl gold-phosphine complex to uncouple mitochondria and inhibit TNBC growth in vivo.