Recapitulating the tumor microenvironment is a central challenge in the development of experimental model for cancer. To provide a reliable tool for drug development and for personalized cancer therapy, it is critical to maintain key features that exist in the original tumor. Along with this effort, 3-dimentional (3D) cellular models are being extensively studied. Spheroids are self-assembled cell aggregates that possess many important components of the physiological spatial growth and cell-cell interactions. In this study we aimed to investigate the interconnection between tumor and endothelial cells (EC) in hybrid spheroids containing either tumor cell (TC) lines or patient derived cancer cells. Preparation protocols of hybrid spheroids were optimized and their morphology and tissue-like features were analyzed. Our finding show that capillary-like structures are formed upon assembly and growth of TC:EC spheroids and that spheroids’ shape and surface texture may be an indication of spatial invasiveness of cells in the extra-cellular matrix (ECM). Establishing a model of hybrid tumor/stroma spheroids has a crucial importance in the experimental approach for personalized medicine, and may offer a reliable and low-cost method for the goal of predicting drug effects.
Metastatic spread is the leading cause for cancer-related mortality, with the lungs being a major site for metastatic seeding. Available therapies for patients with metastatic disease are extremely limited. Therefore, there is a desperate need for new strategies to prevent or limit metastatic dissemination and treat existing metastases. The metastatic cascade is highly complex and is affected by multiple factors related to both tumor cells themselves and the microenvironment in the future site of metastasis. We hypothesized that modifying the lung microenvironment by blocking central ubiquitous signals may affect metastatic seeding in the lungs. Given the high basal levels of the Receptor for Advanced Glycation End products (RAGE) in the pulmonary tissue, and its pro-inflammatory properties, we investigated the consequences of interfering with its ligand; High Mobility Group Box 1 (HMGB1). To this end, we tested the effect of Carbenoxolone, an HMGB1 antagonist, on primary tumor growth and metastatic progression in several murine tumor models. We show that antagonizing HMGB1 prevents the adhesion and colonization of cancer cells in the lungs through the reduction of their adhesion and cell–cell interaction both in vitro and in vivo. We demonstrated that these activities are mediated by downregulation of the adhesion molecule Intercellular Adhesion Molecule 1 (ICAM1) and ultimately result in reduced metastatic burden. Carbenoxolone decreases significantly lung metastases formation and can be used potentially as prophylactic therapy for metastatic diseases.
We suggest that tumor cell-derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.
Carbenoxolone is an anti-inflammatory compound and a derivate of a natural substance from the licorice plant. We previously showed that carbenoxolone reduces the metastatic burden in the lungs of mice through its antagonistic effect on high mobility group box 1 (HMGB1). To further enhance carbenoxolone’s activity and localization in the lungs, thereby reducing the potential adverse side effects resulting from systemic exposure, we developed a poly(lactic-co-glycolic acid) (PLGA) slow-release system for pulmonary delivery which maintains drug activity in-vitro, as demonstrated in the anoikis assay. Both systemic and intranasal administrations of carbenoxolone effectively minimize metastatic formation in a lung colonization model in mice. Our results show a decrease in the metastatic burden in the lung tissue. Notably, the therapeutic effect of a single intranasal administration of 25 mg/kg carbenoxolone, in the form of drug-loaded particles, had a similar effect in reducing metastatic lesions in the lungs to that of a 10-fold dose of the free drug via intraperitoneal injections, three times per week over the course of four weeks. These data offer new means to potentiate the anti-cancer activity of carbenoxolone and simultaneously reduce the requirement for high dosage administration; the upshot substantially improves therapeutic effect and avoidance of side effects.
Amiodarone is an anti-arrhythmic drug that was approved by the US Food and Drug Administration (FDA) in 1985. Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. However, it is also known to cause a variety of severe side effects. We hypothesized that in addition to the cytotoxic effects observed in cancer cells Amiodarone also has an indirect effect on angiogensis, a key factor in the tumor microenvironment. In this study, we examined Amiodarone's effects on a murine tumor model comprised of U-87 MG glioblastoma multiforme (GBM) cells, known to form highly vascularized tumors. We performed several in vitro assays using tumor and endothelial cells, along with in vivo assays utilizing three murine models. Low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect, suggesting dual cancer fighting properties. Our findings lay the ground for further research of Amiodarone as a possible clinical agent that, used in safe doses, maintains its dual properties while averting the drug’s harmful side effects.
Background: Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. In this study, we examined Amiodarone's effects on glioblastoma multiforme (GBM), a highly aggressive and hypervascularized cancer. We hypothesized that Amiodarone would show an anti-angiogenic effect on GBM in addition to its previously suggested anti-cancer activity, and that an ultra-low dose would be both effective and possibly avert the drug’s side effects. Methods: The anti-cancer activity of Amiodarone was assessed by several in vitro assays using GBM cells. This included cytotoxicity, proliferation, transwell migration, Anoikis, colony-formation and three-dimensional (3D) spheroid growth assays. The anti-angiogenic effect of Amiodarone was tested on endothelial cells, using toxicity, proliferation, migration and tube formation in vitro assays. The anti-cancer and anti-angiogenic activity of Amiodarone was examined in vivo on three different murine models. C57BL/6J mice were utilized for the corneal neovascularization model and the Matrigel plug assay. Foxn1 nu mice were inoculated with GBM cells and used for the GBM tumor xenograft model.Results: In this study, we showed that Amiodarone has a significant anti-cancer and anti-angiogenic activity in vitro. Moreover, ultra-low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect in vivo. Conclusions: Our results strongly suggest that Amiodarone possess dual cancer fighting properties.
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