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Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug

Authors
Sharma, AmitLee, Min-GooShi, HuWon, MiaeArambula, Jonathan F.Sessler, Jonathan L.Lee, Jin YongChi, Sung-GilKim, Jong Seung
Issue Date
11-10월-2018
Publisher
CELL PRESS
Keywords
bioenergetics; cancer metabolism; carboxylesterase; dichloroacetic acid; doxorubicin; multidrug resistance; prodrug; SDG3: Good health and well-being; targeted therapeutics; Warburg effect
Citation
CHEM, v.4, no.10, pp.2370 - 2383
Indexed
SCIE
SCOPUS
Journal Title
CHEM
Volume
4
Number
10
Start Page
2370
End Page
2383
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/72492
DOI
10.1016/j.chempr.2018.08.002
ISSN
2451-9294
Abstract
Nearly without exception, all known cancer chemotherapeutics elicit a resistance response over time. The resulting resistance is correlated with poor clinical outcomes. Here, we report an approach to overcoming resistance through reprogramming oncogene-directed alterations in mitochondrial metabolism before drug activation while simultaneously circumventing drug efflux pumps. Conjugate Cl increases cancer cell apoptosis and inhibits regrowth of drug-resistant tumors, as inferred from efficacy studies carried out in human cancer cells and in Dox-resistant xenograft tumor models. It also displays minimal whole-animal toxicity. These benefits are ascribed to an ability to evade chemo-resistance by switching cancer cell metabolism back to normal mitochondrial oxidative phosphorylation while helping target the active Dox to first the mito-chondrion and then the nucleus.
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