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Title: Mitochondria-Targeting Type-I Photodrug: Harnessing Caspase-3 Activity for Pyroptotic Oncotherapy
Authors: Zhigao Yi 
Xujuan Qin
Li Zhang
Huan Chen
Tianlin Song
Zichao Luo 
Tao Wang 
Junwei Lau
Yelin Wu
Tan Boon Toh
Chun-Sing Lee
Wenbo Bu
Xiaogang Liu 
Issue Date: 20-Mar-2024
Publisher: American Chemical Society
Citation: Zhigao Yi, Xujuan Qin, Li Zhang, Huan Chen, Tianlin Song, Zichao Luo, Tao Wang, Junwei Lau, Yelin Wu, Tan Boon Toh, Chun-Sing Lee, Wenbo Bu, Xiaogang Liu (2024-03-20). Mitochondria-Targeting Type-I Photodrug: Harnessing Caspase-3 Activity for Pyroptotic Oncotherapy. Journal of the American Chemical Society 146 (13) : 9413–9421. ScholarBank@NUS Repository.
Abstract: Precise control of cellular signaling events during programmed cell death is crucial yet challenging for cancer therapy. The modulation of signal transduction in cancer cells holds promise but is limited by the lack of efficient, biocompatible, and spatiotemporally controllable approaches. Here we report a photodynamic strategy that modulates both apoptotic and pyroptotic cell death by altering caspase-3 protein activity and the associated signaling crosstalk. This strategy employs a mitochondria-targeting, near-infrared activatable probe (termed M-TOP) that functions via a type-I photochemical mechanism. M-TOP is less dependent on oxygen and more effective in treating drug-resistant cancer cells, even under hypoxic conditions. Our study shows that higher doses of M-TOP induce pyroptotic cell death via the caspase-3/gasdermin-E pathway, whereas lower doses lead to apoptosis. This photodynamic method is effective across diverse gasdermin-E-expressing cancer cells. Moreover, the M-TOP mediated shift from apoptotic to pyroptotic modulation can evoke a controlled inflammatory response, leading to a robust yet balanced immune reaction. This effectively inhibits both distal tumor growth and postsurgical tumor recurrence. This work demonstrates the feasibility of modulating intracellular signaling through the rational design of photodynamic anticancer drugs.
Source Title: Journal of the American Chemical Society
ISSN: 0002-7863
DOI: 10.1021/jacs.4c01929
Appears in Collections:Staff Publications

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