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Scientific article
Open access
English

Identification of a Synergistic Multi-Drug Combination Active in Cancer Cells via the Prevention of Spindle Pole Clustering

Published inCancers, vol. 11, no. 10, 1612
Publication date2019
Abstract

A major limitation of clinically used cancer drugs is the lack of specificity resulting in toxicity. To address this, we performed a phenotypically-driven screen to identify optimal multidrug combinations acting with high efficacy and selectivity in clear cell renal cell carcinoma (ccRCC). The search was performed using the Therapeutically Guided Multidrug Optimization (TGMO) method in ccRCC cells (786-O) and nonmalignant renal cells and identified a synergistic low-dose four-drug combination (C2) with high efficacy and negligible toxicity. We discovered that C2 inhibits multipolar spindle pole clustering, a survival mechanism employed by cancer cells with spindle abnormalities. This phenotype was also observed in 786-O cells resistant to sunitinib, the first line ccRCC treatment, as well as in melanoma cells with distinct percentages of supernumerary centrosomes. We conclude that C2-treatment shows a high efficacy in cells prone to form multipolar spindles. Our data suggest a highly effective and selective C2 treatment strategy for malignant and drug-resistant cancers. View Full-Text

Keywords
  • Drug combinations
  • Drug synergy
  • Centrosome
  • Multipolar spindle pole clustering
Funding
  • Autre - Novartis Foundation of Medical-Biological Research (17A003)
  • European Commission - Optimized drug combinations for effective cancer treatment: a personalised approach. [680209]
Citation (ISO format)
WEISS, Andrea et al. Identification of a Synergistic Multi-Drug Combination Active in Cancer Cells via the Prevention of Spindle Pole Clustering. In: Cancers, 2019, vol. 11, n° 10, p. 1612. doi: 10.3390/cancers11101612
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Identifiers
ISSN of the journal2072-6694
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Creation10/24/2019 2:27:00 PM
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