RESUMEN

The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.

Asunto(s)

Factor de Crecimiento Epidérmico/deficiencia , Silenciador del Gen , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , ARN Interferente Pequeño/genética , Receptores Acoplados a Proteínas G/deficiencia , Receptores de Péptidos/deficiencia , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Muerte Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/biosíntesis , Factor de Crecimiento Epidérmico/genética , Silenciador del Gen/efectos de los fármacos , Glioblastoma/genética , Humanos , ARN Interferente Pequeño/farmacología , Receptores Acoplados a Proteínas G/biosíntesis , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/biosíntesis , Receptores de Péptidos/genética

RESUMEN

BACKGROUND: Plant extract therapy has been the cornerstone of cancer treatment for many years. The natural component curcumin demonstrated antineoplastic effects on different type of tumor cells. In this study, we explored the effectiveness of curcumin against low-passage human primary glioblastoma (GB) cell cultures. MATERIALS AND METHODS: Early passage GB cell cultures (GB3B, GB4B, and GB5B) were established from fresh samples tissue obtained from GB patients. Growth rate (GR) and doubling time (DT) was determined for each cell line. The cytotoxic effect of curcumin was quantified by hemocytometer cell counting, using trypan blue. To study the changes in cell shape, GB cells exposed to a concentration corresponding to inhibitory concentration 50 (IC50) of curcumin were studied by phase-contrast microscopy by capturing images during the treatment. RESULTS: Our results showed that GB cells proliferate with a GR of 0.2872 and a DT of 2.41 days for GB3B, a GR of 0.2787 and a DT of 2.49 days for GB4B, and a GR of 0.2787 and a DT of 2.49 days for GB5B. Curcumin induced cell death in GB cells in a time- and dose-dependent manner. The IC50 for GB3B was 46.4 µM, for GB4B was 78,3 µM, and for GB5B was 47.7 µM. Phase contrast microscopy showed that cultures treated with curcumin in a concentration corresponding to IC50 contained rounded cells and cell fragments, 72 h after the treatment. CONCLUSIONS: The results of the present investigation proved that curcumin is a natural compound potentially useful in the fight against GB.

Asunto(s)

Antineoplásicos/farmacología , Curcumina/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glioblastoma , Humanos , Células Tumorales Cultivadas

RESUMEN

Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), an orphan adhesion G-protein coupled receptor, was reported as a regulator of angiogenesis, also involved in cancer progression and development. More recently, ELTD1 was identified as a potential new tumor marker for high-grade glioma. ELTD1, belongs to the G-protein coupled receptor superfamily that comprises the biggest receptor family in the human genome. Following the discovery of ELTD1 almost a decade ago, only a few research groups have attempted to find its role in normal and tumor cells, important information about this receptor remaining still unknown. The ELTD1 ligand has not currently been identified and intracellular signaling studies have not yet been performed in normal or tumor cells. Although the current published data on ELTD1 function and structure are rather limited, this receptor seems to be very important, not only as biomarker, but also as molecular target in glioblastoma. This review summarizes and discusses the current knowledge on ELTD1 structure, function, and its role in both physiological and tumoral angiogenesis.