In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index

Scientific Reports
M KashifM G Gustafsson

Abstract

In vitro-based search for promising anti-cancer drug combinations may provide important leads to improved cancer therapies. Currently there are no integrated computational-experimental methods specifically designed to search for combinations, maximizing a predefined therapeutic index (TI) defined in terms of appropriate model systems. Here, such a pipeline is presented allowing the search for optimal combinations among an arbitrary number of drugs while also taking experimental variability into account. The TI optimized is the cytotoxicity difference (in vitro) between a target model and an adverse side effect model. Focusing on colorectal carcinoma (CRC), the pipeline provided several combinations that are effective in six different CRC models with limited cytotoxicity in normal cell models. Herein we describe the identification of the combination (Trichostatin A, Afungin, 17-AAG) and present results from subsequent characterisations, including efficacy in primary cultures of tumour cells from CRC patients. We hypothesize that its effect derives from potentiation of the proteotoxic action of 17-AAG by Trichostatin A and Afungin. The discovered drug combinations against CRC are significant findings themselves and also indicate ...Continue Reading

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Citations

Oct 1, 2019·Anti-cancer Agents in Medicinal Chemistry·Kikoleho RichaUpasana B Sinha
Mar 21, 2019·Scientific Reports·Christoph EilenbergerSeta Küpcü
Aug 6, 2019·Frontiers in Chemistry·Pavel SidorovPedro J Ballester
Oct 29, 2017·Journal of Ovarian Research·Frank Christian KischkelJalid Sehouli
May 15, 2021·Mutation Research. Genetic Toxicology and Environmental Mutagenesis·Fotini PapachristouAlexandra Tsaroucha
Aug 10, 2021·Briefings in Bioinformatics·Chayanit PiyawajanusornPedro J Ballester

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Software Mentioned

BioScript Pro
Matlab
ArrayScan VTI Reader
: Profiler
MACS ( Medicinal Algorithmic Combinatorial Screen )
MetaCore
Excel
Tool Command Language ( TCL )
TACS
Nextbio

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