Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 14, Pages 4638-4643Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201900387
Keywords
antitumor agents; metabolism; mitochondria; platinum; thioredoxin reductase
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Funding
- National Natural Science Foundation of China [31700714, 31570809, 21877059]
- National Basic Research Program of China [2015CB856300]
- Natural Science Foundation of Jiangsu Province [BK20150054]
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Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As a result, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cancer cells to enter a hypometabolic state.
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