Overcoming paclitaxel resistance in ovarian cancer cells using DN200434, an inverse agonist of estrogen-related receptor gamma (ERRγ).

Ovarian cancer is one of the most prevalent gynecological malignancies in women. Resistance towards frontline chemotherapy, paclitaxel is a major obstacle in the management of cancer. This intricate phenomenon reduces the treatment efficacy, leading to poor patient prognosis. Recently, the nuclear receptor estrogen-related receptor γ (ERRγ) has been implicated in cancer progression and metastasis. In particular, the receptor is reported to be overexpressed in ovarian cancer, and its overexpression is associated with reduced overall survival. However, the effect of ERRγ targeting using the selective inverse agonist DN200434 on ovarian cancer progression remains to be explored. In this study, we report dose-dependent inhibition of SKOV-3 progression and parallel induction of apoptosis with DN2000434. Further, the potential of receptor targeting in sensitization towards taxol is shown in resistant SKOV-3 cells. The combination of DN200434 and paclitaxel induced resistance reversal via augmentation of cell cycle arrest and apoptosis. This phenomenon was corroborated in a 3-D agarose-based spheroid model.