Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 38, Pages 11539-11544Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201706739
Keywords
anticancer drugs; KRAS mutated cancer cells; multi-action drugs; platinum; prodrugs
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Funding
- Israel Science Foundation [1611/14]
- University of Padova [60A04-0443, 60A04-3189, 60A04-4015/15]
- Lady Davis Fellowship (Mary Heller Legacy Scholarship)
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We developed a novel Pt-IV prodrug that simultaneously releases four different bioactive moieties inside the cancer cell. Its cytotoxicity against monolayer cultures (2D) and spheroid (3D) cancer cells is significantly better than cisplatin. It is 200-450-fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40-fold more selective towards KRAS mutated cells compared to non-cancerous. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90% of pancreatic adenocarcinomas, 45% of colorectal cancers, and 35% of lung adenocarcinomas. The selectivity index, determined by dividing the IC50 value in non-cancerous cells by that of a cancerous cell line, is two-fold better than cisplatin, attesting to preferential cytotoxicity towards neoplastic cells.
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