PlatinER: A Highly Potent Anticancer Platinum(II) Complex that Induces Endoplasmic Reticulum Stress Driven Immunogenic Cell Death |
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Authors: | Max Jing Rui Tham Dr. Maria V. Babak Prof. Wee Han Ang |
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Affiliation: | 1. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 21 Lower Kent Ridge Road, 119077 Singapore, Singapoare;2. Department of Chemistry, National University of Singapore, 3 Science Drive 2, 117543 Singapore, Singapore |
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Abstract: | Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo-immunotherapeutic combination regimens through the establishment of a long-term cancer immunity. None of the clinically used DNA-binding PtII complexes is considered a Type II ICD inducer. We generated a series of PtII-carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt-NHC and compared their efficiency in triggering ICD-related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent PtII candidate with superior ICD properties. Crucially, the magnitude of ICD-associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER-localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. |
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Keywords: | antitumor agents drug discovery immunochemotherapy immunogenic cell death platinum |
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