Effects of WIN 55,212 cannabinoid and SMA-WIN 55,212 on the expression of cannabinoid receptors in different glioma cell lines.

Abstract Background: Glioblastoma (GBM) is a highly invasive primary malignancy of the brain that is prone to acquiring resistance to chemotherapy. Given the limited therapeutic options available, an unmet need exists for effective treatment of GBM. In the present study, we evaluated the in vitro anticancer activity of WIN 55,212 (WIN), a synthetic cannabinoid molecule, in the form of micelles conjugated with styrene-maleic acid (SMA) against the LN 18 (epithelial origin) and A172 (mesenchymal origin) glioma cell lines. Methods: SMA–WIN 55,212-2 micelles were prepared in vitro using a pre-validated, standard technique. The cytotoxic effects of the two treatments (WIN 55,212-2 and SMA-WIN 55,212-2) were evaluated in glioma cell lines (LN-18 and A-172), and inhibitory concentrations for killing 50% of the cells (IC50) were estimated. The expression of the CB1 (cannabinoid receptor 1), CB2 (cannabinoid receptor 2), TRPV1 (transient receptor potential vanilloid 1), and PPAR-γ (peroxisome proliferator-activated receptor gamma) receptors following treatment with the free and micellar forms of WIN 55,212-2 was detected. Results: We observed significantly lower IC50 values for both the LN 18 and A172 cell lines with SMA-WIN 55 and 212-2 than with WIN 55 and 212-2 alone. Similarly, the expression of the CB1 and CB2 receptors was significantly greater in the SMA-WIN 55 and 212-2 cell lines than in the WIN 55 and 212-2 cell lines in the A172 cell line. No significant changes were observed for TRPV1, while only SMA-WIN 55,212-2 increased the expression of PPAR-γ receptors. Conclusion: The micellar formulation of WIN 55 and 212-2 had significantly greater effects on both glioma cell lines than did the free WIN 55 and 212-2. The formulations of WIN 55 and 212-2 exhibited variable cannabinoid receptor expression levels and need further evaluation in suitable in vivo animal models. Moreover, SMA-WIN 55 and 212-2 significantly upregulate PPAR-γ, which requires further investigation.