Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma.

Details

Serval ID
serval:BIB_3704D6CA4FBB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma.
Journal
Cancers
Author(s)
Rausch M., Rutz A., Allard P.M., Delucinge-Vivier C., Docquier M., Dormond O., Dyson P.J., Wolfender J.L., Nowak-Sliwinska P.
ISSN
2072-6694 (Print)
ISSN-L
2072-6694
Publication state
Published
Issued date
06/08/2021
Peer-reviewed
Oui
Volume
13
Number
16
Pages
3978
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.
Keywords
Rapta-C, drug combination, drug repurposing, drug-drug interaction, metabolism, metformin, synergistic
Pubmed
Web of science
Open Access
Yes
Create date
03/09/2021 19:12
Last modification date
23/02/2022 7:36
Usage data