Papel do receptor P2Y12 na proliferação e na migração de linhagens de glioma e culturas primárias humanas

Abstract

Glioblastoma multiforme (GBM) is considered the most aggressive of central nervous system (CNS) tumors and the most lethal among primary tumors, with a short survival time, resistance to radiotherapy and chemotherapy. P2Y12 is an adenosine diphosphate (ADP) chemoreceptor, and its expression is documented in some cancer cell lines, such as the C6 line of rat glioma, renal carcinoma and colon carcinoma. Its role in the development of signaling and response to chemotherapy is not well understood, but it is a receptor whose activation induces cell proliferation and which, because it is expressed in platelets and promotes its activation, facilitates the process of metastasis. Ticagrelor is a drug belonging to the class of antiplatelet agents, antagonist of the P2Y12 receptor, already approved and commercialized. Bearing in mind the previous findings and the need to find new treatments for gliomas, this work aimed to study the role of the P2Y12 receptor in proliferation, invasion and migration in cell lines and primary glioma cells, as well as to develop a formulation of polymeric nanoparticles. For this, two types of cells were used: glioma cell lines, and primary human glioma cultures. The different cells were treated with the selective P2Y12R antagonist, ticagrelor, with the agonist, ADP, or with both and the effects on the following parameters were evaluated: cell proliferation, colony formation potential, ADP hydrolysis, cell cycle and cell death, migration and cell adhesion. The results showed that ticagrelor has decreased viability and proliferation in the glioma cells studied, and this effect was not reversed by ADP. P2Y12R antagonism reduced the potential for colony formation and migration and induced cells to autophagy in the three cell types of glioma. No changes were observed at the cell cycle level, and only the U251-MG strain showed a significant reduction in the hydrolysis profile of ADP. However, the expression of MMPs and P2Y12 were altered in all tested cells, when exposed to ticagrelor. In addition, a white nanoparticle was produced and characterized for further encapsulation of ticagrelor to enhance the response and reduce the dose required to obtain the desired pharmacological effect. Thus, although more studies are needed, the results point to the potential for repositioning ticagrelor for the treatment of glioblastoma.