Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 35, Issue 1, Pages 665-671Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2020.1734800
Keywords
Anticancer agents; carbonic anhydrase inhibition; thioredoxin reductase inhibition; synergistic effect; dual pharmacophores; Michael acceptors; zinc-binding group; hypoxia; oxidative stress; cancer cell defence mechanisms
Funding
- Russian Foundation for Basic Research [19-33-90017]
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A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell's defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design.
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