A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines

Emanuele Petruzzella; Jeremy Phillip Braude; Janice R. Aldrich-Wright; Valentina Gandin; Dan Gibson

doi:10.1002/anie.201706739

A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines

Emanuele Petruzzella
, Jeremy Phillip Braude
, Janice R. Aldrich-Wright
, Valentina Gandin
, Dan Gibson^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

110 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	11539-11544
Number of pages	6
Journal	Angewandte Chemie - International Edition
Volume	56
Issue number	38
DOIs	https://doi.org/10.1002/anie.201706739
State	Published - 11 Sep 2017

Bibliographical note

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

KRAS mutated cancer cells
anticancer drugs
multi-action drugs
platinum
prodrugs

Access to Document

10.1002/anie.201706739

Cite this

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title = "A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines",

abstract = "We developed a novel PtIV 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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AU - Gandin, Valentina

AU - Gibson, Dan

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KW - multi-action drugs

KW - platinum

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A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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