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.
Highlights
Metal-based chemotherapeutics including cisplatin, carboplatin and oxaliplatin have been used routinely in the clinic for decades and continue to represent the mainstay of treatment for many cancer types[1]
Measurement of absolute cell numbers in A2780 and A2780cisR cells showed that the cell count for erlotinib/RAPTA-C treated cells did not increase much whereas the cell count of non-treated cells tripled after 72 hours (Fig. 1B)
This difference suggests that erlotinib/RAPTA-C combinations induce a state of cellular senescence, as the cell number does not decrease
Summary
Metal-based chemotherapeutics including cisplatin, carboplatin and oxaliplatin have been used routinely in the clinic for decades and continue to represent the mainstay of treatment for many cancer types[1]. While the mechanism of action of RAPTA-C still remains to be fully elucidated, it has been suggested that the formation of adducts in chromatin histone proteins are involved[18] This mechanism is different to that observed for the ruthenium(III) compounds mentioned above[19,20,21]. Combinations of NAMI-A and 5-fluorouracil, cisplatin or doxorubicin showed superior activity compared to either chemotherapeutic alone in various pre-clinical cancer models[31,32,33]. In a recent phase I/II trial in NSCLC patients, NAMI-A and gemcitabine did not show enhanced activity[13] Another Ru-based compound, KP1339, was recently found to synergistically improve the effect of the multi-kinase inhibitor sorafenib in hepatoma cancer in vitro and in vivo[26]. This study hinted towards dose-dependent synergistic interactions between RAPTA-C and the epidermal growth factor receptor (EGFR)
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