Comparison of Sonidegib and Vismodegib Efficiency in Drug-Sensitive and Resistant Ovarian Cancer Cell Lines—2D and 3D Model Study

Ovarian cancer is a leading cause of mortality among gynecological malignancies. Despite the initial effectiveness of chemotherapy, multidrug resistance (MDR), driven by ABC transporters such as P-glycoprotein, limits treatment success by reducing intracellular paclitaxel (PAC) accumulation. Abnormalities in the Cancer Stem Cells signaling pathway Sonic Hedgehog (Shh) play a role in drug resistance development and ovarian cancer progression. We evaluated two Shh pathway inhibitors, Sonidegib (LDE225) and Vismodegib (VIS), in the W1 drug-sensitive ovarian cancer cell line and PAC-resistant sublines, using the 2D monolayer model, as well as the 3D spheroid model, to better simulate conditions of the tumor microenvironment. qPCR analysis showed similar levels of Shh pathway gene expression in 2D and 3D cell culture conditions. PAC-resistant cell lines were 3- to 6-fold more sensitive to both LDE225 and VIS than the PAC-sensitive cell line. LDE225 showed a 6- to 10-fold lower IC50 than Vismodegib, indicating higher potency. Both agents inhibited proliferation and colony formation in a concentration-dependent manner. Differences in IC50 between 2D and 3D dense spheroids formed by the W1 cell line were small, suggesting that high spheroid density does not reduce the activity of LDE225 and VIS against cancer cells. In conclusion, both inhibitors present pleotropic effects against ovarian cancer cells, especially drug-resistant ones, and can be considered as a new treatment opportunity in this cancer. Nevertheless, further investigation of Hedgehog pathway inhibition in more advanced models is required to assess the potential of clinical application for these compounds.