Osthole promotes the suppressive effects of cisplatin on NRF2 expression to prevent drug-resistant cervical cancer progression

Abstract

Cervical cancer is one of the most commonly diagnosed lethal malignancies among gynecological malignant tumors worldwide. Chemo-resistance is one of the key causal factors in cervical cancer death. Osthole (OST), a natural compound, exhibits various pharmacological activities, including anti-tumor effects. However, its involvement in the chemoresistance of human cervical cancer has not been reported. In the study, we aimed to clarify the role of OST in regulating the chemoresistance of human cervical cancer. The results indicated that cisplatin (CDDP) combined with OST markedly reduced the cell proliferation and induced cervical cancer cells undergoing apoptosis when compared to CDDP alone treatment. In CDDP-resistant cervical cancer cells, OST significantly decreased nuclear factor, erythroid 2 like 2 (NRF2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC) expression levels from mRNA or protein levels. Additionally, through combination with CDDP, OST dose- and time-dependently reduced NRF2 expression in CDDP-resistant cervical cancer cells. Moreover, we found that CDDP co-treated with OST significantly blocked phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathway. Importantly, CDDP combined with LY294002, inhibitor of phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling, markedly decreased the expression of NRF2, HO-1, NQO1 and GCLC in drug-resistant cervical cancer cells. The in vivo study also suggested that OST in combination obviously reduced tumor growth in comparison to the CDDP alone group. Taken together, these findings indicated that OST could be used as a potential sensitizer to reverse chemoresistance of cisplatin-resistant cervical cancer to cisplatin through repressing NRF2 expression partly associated with PI3K/AKT blockage.