Anti-Cancer Stem Cell Cobalt(III)-Polypyridyl Complexes Containing Salicylic Acid

Abstract

Metal-containing compounds are an important class of chemotherapeutics used to treat various manifestations of cancer. Despite the widespread clinical use and success of metallopharmaceuticals, they are ineffective towards a sub-population of tumours called cancer stem cells (CSCs). CSCs evade current chemotherapeutic regimens (including metallopharmaceuticals) and promote cancer relapse and metastasis. Here, we report the synthesis, characterisation and anti-breast CSCs properties of a series of cobalt(III)-polypyridyl complexes with salicylic acid. The lead cobalt(III) complex 6 (containing 3,4,7,8-tetramethyl-1,10-phenanthroline) displayed low micromolar potency towards breast CSCs, significantly lower than the gold-standard anti-breast CSC agent, salinomycin, and the clinically used metallodrug, cisplatin. Mechanistic studies indicate that the cobalt(III) complex 6 induces its anti-breast CSC effect by entering breast CSCs, penetrating the nuclei, damaging nuclear DNA and triggering caspase-dependent apoptosis. The cytotoxic mechanism of action of the cobalt(III) complex 6 is also dependent on the modulation of cyclooxygenase-2 (COX-2) expression. This work highlights the anti-breast CSC properties of cobalt(III) coordination complexes with non-steroidal anti-inflammatory drugs (NSAIDs) and more widely spotlights the importance of metallopharmaceuticals in the development of new anticancer agents that can tackle chemotherapeutic-resistant sub-populations.