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Combination of ruthenium(II)-arene complex [Ru(η6-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity

Berndsen, Robert H
Weiss, Andrea
Abdul, U Kulsoom
Wong, Tse J
Griffioen, Arjan W
Dyson, Paul J
Published in Scientific reports. 2017, vol. 7, 43005
Abstract Ruthenium-based compounds show strong potential as anti-cancer drugs and are being investigated as alternatives to other well-established metal-based chemotherapeutics. The organometallic compound [Ru(η6-p-cymene)Cl2(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C) exhibits broad acting anti-tumor efficacy with intrinsic angiostatic activity. In the search for an optimal anti-angiogenesis drug combination, we identified synergistic potential between RAPTA-C and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. This drug combination results in strong synergistic inhibition of cell viability in human endothelial (ECRF24 and HUVEC) and human ovarian carcinoma (A2780 and A2780cisR) cells. Additionally, erlotinib significantly enhances the cellular uptake of RAPTA-C relative to treatment with RAPTA-C alone in human ovarian carcinoma cells, but not endothelial cells. Drug combinations induce the formation of chromosome bridges that persist after mitotic exit and delay abscission in A2780 and A2780cisR, therefore suggesting initiation of cellular senescence. The therapeutic potential of these compounds and their combination is further validated in vivo on A2780 tumors grown on the chicken chorioallantoic membrane (CAM) model, and in a preclinical model in nude mice. Immunohistochemical analysis confirms effective anti-angiogenic and anti-proliferative activity in vivo, based on a significant reduction of microvascular density and a decrease in proliferating cells.
Keywords AnimalsAntineoplastic Agents/chemistry/pharmacology/therapeutic useCell LineTumorCell Movement/drug effectsCell Survival/drug effectsCellular Senescence/drug effectsChickensChorioallantoic Membrane/drug effects/physiologyCymenesDrug ResistanceNeoplasm/drug effectsDrug SynergismDrug TherapyCombinationErlotinib Hydrochloride/chemistry/pharmacology/therapeutic useFemaleHuman Umbilical Vein Endothelial CellsHumansMiceMiceNudeNeovascularizationPhysiologic/drug effectsOrganometallic Compounds/chemistry/pharmacology/therapeutic useOvarian Neoplasms/drug therapy/pathology
PMID: 28223694
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Article (Published version) (2.5 MB) - public document Free access
Research groups Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) (922)
Pharmacologie moléculaire
Swiss National Science Foundation: 31003A_160006
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BERNDSEN, Robert H et al. Combination of ruthenium(II)-arene complex [Ru(η6-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity. In: Scientific Reports, 2017, vol. 7, p. 43005. doi: 10.1038/srep43005 https://archive-ouverte.unige.ch/unige:138146

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Deposited on : 2020-07-01

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