The
platinum(IV)
prodrug trans,trans,trans-[Pt(N3)2(
OH)2(py)2] (1) is stable and non-toxic in the dark, but potently cytotoxic to
cancer cells when irradiated by visible light, including
cisplatin-resistant cells. On irradiation with visible light, it generates reactive Pt(II) species which can attack
DNA, and produces
reactive oxygen species (ROS) and
reactive nitrogen species (RNS) which exert unusual effects on biochemical pathways. We now show that its novel mechanism of action includes induction of immunogenic cell death (ICD). Treatment of
cancer cells with 1 followed by photoirradiation with visible light induces
calreticulin (CRT) expression at the surface of dying
cancer cells. This is accompanied by release of high mobility group protein-1B (
HMGB1) and the secretion of
ATP. Autophagy appears to play a key role in this chemotherapeutically-stimulated ICD. The observed uneven distribution of ecto-CRT promotes phagocytosis, confirmed by the observation of engulfment of photoirradiated CT26
colorectal cancer cells treated with 1 by J774.A1 macrophages. The photoactivatable
prodrug 1 has a unique mechanism of action which distinguishes it from other
platinum drugs due to its immunomodulating properties, which may enhance its anticancer efficacy.