Necroptosis-inducing iridium(iii) complexes as regulators of cyclin-dependent kinases

Abstract

Necroptosis has emerged as an important mode of programmed cell death (PCD), which can be enhanced by cell cycle arrest. As an alternative destruction mode in cancer therapy, necroptosis induced by chemotherapeutic agents can be a powerful weapon in combating drug-resistant cancers. Herein, two iridium(III) complexes, NecroIr1 and NecroIr2, were synthesized as necroptosis inducers in cisplatin-resistant lung cancer cells (A549R). NecroIr1 and NecroIr2 selectively accumulated in mitochondria, leading to oxidative stress and loss of mitochondrial membrane potential (MMP). Necroptosis induced by the Ir(III) complexes was characterized by the annexin V/propidium iodide costaining assay and western blot, the results of which showed the activation of receptor-interacting serine–threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). Other necroptotic events, such as extracellular calcium influx and leakage of lactate dehydrogenase (LDH), were observed, thus confirming NecroIr1 and NecroIr2 as necroptosis inducers in A549R cells. Most importantly, NecroIr1 and NecroIr2 interfered with the progression of the cell cycle and caused cell cycle arrest in the G0/G1 phase by the downregulation of cyclin-dependent kinases (CDK1, CDK2, CDK4 and CDK6) and cyclin A2 and D2. The combined effect of necroptosis and cell cycle arrest makes both NecroIr1 and NecroIr2 potential antitumor agents that circumvent drug-resistant cancer cells.