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Scientific article
Open access
English

Drug repurposing to identify a synergistic high-order drug combination to treat sunitinib-resistant renal cell carcinoma

Published inCancers, vol. 13, no. 16, 3978
Publication date2021-08-06
First online date2021-08-06
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
Citation (ISO format)
RAUSCH, Magdalena et al. Drug repurposing to identify a synergistic high-order drug combination to treat sunitinib-resistant renal cell carcinoma. In: Cancers, 2021, vol. 13, n° 16, p. 3978. doi: 10.3390/cancers13163978
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Identifiers
ISSN of the journal2072-6694
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