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Open AccessArticle

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

1
Institute of Pharmaceutical Sciences of Western Switzerland, Faculty of Sciences, University of Geneva, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland
2
Translational Research Centre in Oncohaematology, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland
3
Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland
4
Department of Pathology and Immunology, University of Geneva Medical School, 1 Rue Michel-Servet, CMU, 1211 Geneva 4, Switzerland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Cancers 2019, 11(10), 1612; https://doi.org/10.3390/cancers11101612
Received: 7 October 2019 / Revised: 14 October 2019 / Accepted: 16 October 2019 / Published: 22 October 2019
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 drug combinations; drug synergy; centrosome; multipolar spindle pole clustering
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Weiss, A.; Le Roux-Bourdieu, M.; Zoetemelk, M.; Ramzy, G.M.; Rausch, M.; Harry, D.; Miljkovic-Licina, M.; Falamaki, K.; Wehrle-Haller, B.; Meraldi, P.; Nowak-Sliwinska, P. Identification of a Synergistic Multi-Drug Combination Active in Cancer Cells via the Prevention of Spindle Pole Clustering. Cancers 2019, 11, 1612.

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