Induction of immunogenic cell death in cancer cells by a photoactivated platinum(IV) prodrug

Vojtech Novohradsky, Jitka Pracharova, Jana Kasparkova, Cinzia Imberti, Hannah E Bridgewater, Peter J Sadler, Viktor Brabec

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4150-4159
Number of pages10
JournalInorganic Chemistry Frontiers
Volume7
Issue number21
Early online date18 Sept 2020
DOIs
Publication statusPublished - 7 Nov 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Czech Science Foundation (Grant 18-09502S), the Wellcome Trust (Grant 209173/Z/17/Z, Fellowship for C. I.), EPSRC (Grants EP/F034210/1 and EP/ P030572/1) and Anglo American Platinum Mike and Enfys Bagguley (PhD Studentship for H. E. B).

Publisher Copyright:
© 2020 the Partner Organisations.

ASJC Scopus subject areas

  • Inorganic Chemistry

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