Andrographolide Mitigates Cisplatin Resistance by Inhibiting SPP1 Regulated NF-kB/iNOS/COX-2 and PI3K/AKT Pathway in Cisplatin Resistant Cervical Carcinoma Cells

Abstract

Drug resistance and cancer recurrence are major cause of Cervical cancer (CC) patient mortality. Cisplatin (CDDP) is the major drug that has been extremely used in all stages in treating CC, although relapse and malignant instances have been observed as a result of cisplatin resistance in CC. In the present study, we established Cisplatin resistant CC HeLa cell line model and the cytotoxic effects of Andro as a single agent or in combination with CDDP were investigated to assess its potential as a chemotherapeutic agent in cisplatin-resistant HeLa (CisR-HeLa) cells. Andro enhanced the cytotoxicity of CDDP in CisR-HeLa cells and shown a synergistic effect by reducing cell viability, proliferation, migration, invasion, and inducing apoptosis in cisplatin resistant cells. Furthermore, we evaluated the expression levels of inflammatory and oncogenic proteins, SPP1, NF-kB, iNOS, COX-2, and the PI3K/AKT signaling pathway, which are associated with cisplatin resistance, as well as using Andro to regulate the targeted markers in CisR-HeLa cells to overcome resistance. The results show that suppressing SPP1 and NF-kB by Andro alone or in combination with CDDP regulates iNOS, COX-2, and increases PTEN expression. The addition of Andro to CDDP inhibited PI3K and AKT expression as well as triggered synergistic apoptosis, which could be associated with variations in Bax and Bcl-2 protein levels. The results suggest that Andro in combination with CDDP exhibits synergistic anti-tumor growth efficacy that targets multiple inflammatory markers, resulting in a promising treatment option for individuals with recurrent cancer due to drug resistance and advanced CC.