Chemotherapy resistance is a major obstacle in the treatment of ovarian cancer, often resulting in disease recurrence and poor prognosis for patients. A key contributor to this resistance is the overexpression of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP/ABCG2), which actively effluxes chemotherapeutic agents such as topotecan (TOP) or mitoxantrone (MIT), limiting their intracellular accumulation and efficacy. This study investigated the potential of elacridar (GG918), a potent dual P-gp and BCRP inhibitor, to overcome drug resistance in ovarian cancer cell lines. Both TOP-sensitive and TOP-resistant ovarian cancer cells were grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroid models to better mimic the tumor microenvironment. The expression of the ABCG2 gene was quantified via qPCR and BCRP protein levels were assessed by western blotting and immunofluorescence. Drug response was evaluated using MTT viability assays, while BCRP transporter activity was examined using flow cytometry and microscopic assessment of the intracellular retention of BCRP fluorescent substrates (Hoechst 33342 and MIT). In both 2D and 3D cultures, elacridar effectively inhibited BCRP function and significantly enhanced sensitivity to TOP. These findings suggest that elacridar can inhibit BCRP-mediated drug resistance in ovarian cancer cell models.

Ovarian cancer remains a leading cause of gynecological cancer-related mortality. Alt-hough the standard therapy is usually effective at first, the development of Multidrug Re-sistance (MDR) significantly limits the efficacy of the treatment. Topotecan (TOP) is a drug commonly used in second-line therapy. However, the cancer cells eventually become im-mune to its cytotoxic effect, as they start to produce ATP-binding cassette (ABC) transport-ers, proteins facilitating drug removal. Breast Cancer Resistance Protein (BCRP) is one such protein, and TOP is its known substrate. Vismodegib, a Sonic Hedgehog pathway (Shh) inhibitor, has demonstrated potential anticancer activity in various malignancies. This study aims to evaluate the effects of Vismodegib treatment on both topotec-an-sensitive and -resistant ovarian cancer cell lines, cultured in two-dimensional (2D) and three-dimensional (3D) conditions, as well as the potential of Vismodegib treatment to re-verse the acquired drug resistance. Our results suggest that Vismodegib re-sensitizes TOP-resistant cells in both 2D and 3D models. However, further research is needed to evaluate its usefulness in ovarian cancer treatment.

Ovarian cancer remains a leading cause of gynecological cancer-related mortality. Although the standard therapy is usually effective at first, the development of multidrug resistance (MDR) significantly limits the efficacy of the treatment. Topotecan (TOP) is a drug commonly used in second-line therapy. However, the cancer cells eventually become immune to its cytotoxic effect, as they start to produce ATP-binding cassette (ABC) transporters, proteins facilitating drug removal. Breast cancer resistance protein (BCRP) is one such protein, and TOP is its known substrate. Vismodegib, a Sonic Hedgehog pathway (Shh) inhibitor, has demonstrated potential anticancer activity in various malignancies. This study aims to evaluate the effects of Vismodegib treatment on both topotecan-sensitive and -resistant ovarian cancer cell lines, cultured in two-dimensional (2D) and three-dimensional (3D) conditions, as well as the potential of Vismodegib treatment to reverse the acquired drug resistance. Our results suggest that Vismodegib re-sensitizes TOP-resistant cells in both 2D and 3D models. However, further research is needed to evaluate its usefulness in ovarian cancer treatment.

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.