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

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Novohradsky, Vojtech, Pracharova, Jitka, Kasparkova, Jana, Imberti, Cinzia, Bridgewater, Hannah E., Sadler, Peter J. and Brabec, Viktor (2020) Induction of immunogenic cell death in cancer cells by a photoactivated platinum(iv) prodrug. Inorganic Chemistry Frontiers, 7 (21). pp. 4150-4159. doi:10.1039/d0qi00991a

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Official URL: http://dx.doi.org/10.1039/d0qi00991a

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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.

Item Type: Journal Article
Subjects: Q Science > QC Physics
R Medicine > RC Internal medicine
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH): Cancer cells , Cancer cells -- Effect of radiation on, Cancer cells -- Effect of drugs on, Prodrugs , Platinum -- Therapeutic use, Irradiation
Journal or Publication Title: Inorganic Chemistry Frontiers
Publisher: RSC
ISSN: 2052-1553
Official Date: 18 September 2020
Dates:
DateEvent
18 September 2020Available
17 October 2020Accepted
Volume: 7
Number: 21
Page Range: pp. 4150-4159
DOI: 10.1039/d0qi00991a
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
18-09502SGrantová Agentura České RepublikyUNSPECIFIED
209173/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
EP/F034210/1 [EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/ P030572/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
UNSPECIFIEDAnglo Platinum (Firm)http://viaf.org/viaf/145251518

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