The study of the molecular mechanism of action of cannabidiol in 2D and 3D in vitro cell models reveals new insights about the translation factor EIF2A

The development of advanced cell culture models has overcome the limitations of conventional monolayer cultures, still doubts remain about the reliability of data obtained using traditional systems, as well as the comparability of results from different models. This is highly relevant to preclinical drug analysis, where in vitro studies determine the fate of molecules. We investigated the molecular mechanisms that regulate the activity of cannabidiolic acid (CBDA) in a 3D model of a glioblastoma cell line, comparing the results with those obtained on a conventional monolayer model of the same cells. CBDA targeted the translation initiation factor EIF2A in both tested models. However, the downstream consequences of the CBDA-EIF2A interaction differed between cells cultured in 3D and 2D, since the biological functions and interactome of EIF2A were found to change significantly. Overall, this study sheds new light on the difficulties associated with comparing results obtained using different in vitro models.