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Induction of Immunogenic Cell Death by Chemotherapeutic Platinum Complexes

2015; Wiley; Volume: 54; Issue: 22 Linguagem: Inglês

10.1002/anie.201500934

1521-3773

Daniel Yuan Qiang Wong, Wendy Wei Fang Ong, Wee Han Ang,

RNA Interference and Gene Delivery

Abstract There is compelling evidence suggesting that the immune‐modulating effects of many conventional chemotherapeutics, including platinum‐based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor‐specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an “anticancer vaccine”. In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A Pt II N‐heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small‐molecule immuno‐chemotherapeutic agent.