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.
Cancer cells are often dependent on epigenetic pathways for their survival. Consequently, drugs that target the epigenome, rather than the underlying DNA sequence, are currently attracting considerable attention. In recent years, the first epigenetic drugs have been approved for cancer chemotherapy, mainly for hematological applications. Limitations in single-drug efficacies have thus far limited their application in the treatment of solid tumors. Nevertheless, promising activity for these compounds has been suggested when combined with other, distinctly targeted agents. In this review, we discuss the anti-angiogenic activity of histone deacetylase and DNA methyltransferase inhibitors and their combinations with other targeted (anti-angiogenic) therapeutics in treatment of solid tumors. The role that these inhibitors play in the inhibition of tumor angiogenesis, particularly in combination with other targeted agents, and the advantages they present over broad acting anticancer agents, are critically discussed.
Angiostatic therapies are now routinely embedded in the daily clinical management of cancer. Although these agents clearly benefit patient survival rates, the effect is only moderate with sometimes considerable side effects. A major cause of failure in this respect is the induction of resistance and tolerability against these drugs. Most angiostatic drugs are tyrosine kinase inhibitors that aim to inhibit or neutralize the activity of tumour-produced growth factors. Frustrating the tumour cells in this way results in genetic adaptations in the cells, turning them into mutants that are dependent on other growth mechanisms. It may therefore be necessary to shift to another class of drugs that directly target the tumour vasculature. It is evident that improvement of future angiogenesis inhibitors can only arise from two efforts. First, through the identification of better targets, preferably specifically expressed in the tumour vasculature. Secondly, through the development of combination therapies. The present review highlights the current efforts and challenges in trying to develop effective angiostatic combination therapies.
Neuroblastoma is a pediatric tumor that originates from cells of the adrenergic lineage. Here we investigated the balance between differentiation and dedifferentiation in relation to tumor-engraftment potential in preclinical mouse models. We analyzed intratumoral heterogeneity through comparison of marker expression of normal adrenergic development versus tumor marker expression, which showed the presence of sympathoadrenal as well as mesenchymal subtypes of neuroblastomas cells. Subsequently, we evaluated long-term outgrowth capacity of these two (FACS-sorted) cell populations, which showed that adrenergic cells have a stronger long-term clonogenic potential. Engraftment of these sorted populations into mice revealed the occurrence of heterogeneous populations. Modelling of the interconversion rate indicated that cell fate transitions from the adrenergic to mesenchymal state were obtained gradually and stochastically as the tumors grew in mice. We found that adrenergic cells have an increased tumorigenic potential in mice without signs of beneficial cross talk between the two lineage populations. These findings indicate that neuroblastoma contains two rivalling differentiation states that exhibit differences in long term clonal/tumorigenic potential. We expect these states to be relevant for therapy resistance as a result of intratumoral heterogeneity.
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