Curcuminoids WM03 inhibits ovarian cancer cisplatin-resistant cells proliferation and reverses cisplatin resistance by targeting DYRK2
Cisplatin is a common chemotherapy agent used to treat ovarian cancer and cisplatin resistance is the most common consequence after its treatment. Curcumin has been shown to effectively inhibit the proliferation and invasion of ovarian cancer cells but its bioavailability restricts its application. The objective of this study was to develop the novel curcumin derivatives with high efficacy and synergic effects with cisplatin to inhibit cisplatin resistant ovarian cancers. Colony formation assay and growth curve assay Were used to detect cell proliferation. Transwell and cell scratch assay Were used to detect cell invasion and migration. Western blot (WB), Immunohistochemistry (IHC) and Immunofluorescence (IF) Were used to detect the expression levels of related molecules. qPCR was used to detect mRNA levels of related molecules. Kinase profile sequencing was used to analyze kinase activity. RNA seq was used to analyze significant signaling pathways. The ability of Surface plasmon resonance (SPR), Isothermal titration calorimetry (ITC) and Cellular Thermal Shift Assay (CESTA), molecular docking to analyze the binding of drugs and molecules; Co-Immunoprecipitation (Co-IP) and confocal are used to analyze intermolecular interactions. Ubiquitination is used to detect ubiquitin levels of related molecules; Animal experiments are used to simulate clinical validation RESULTS: Four curcumin derivatives Were synthesized and evaluated to treat ovarian cancers. Curcumin derivative WM03 was the most effective to inhibit A2780DR and HO8910PMDR cell proliferation with about 8-12 times more potent than curcumin. WM03 inhibited A2780DR and HO8910PMDR cell proliferation, migration, and invasion with a synergic effect of cisplatin for cisplatin resistant ovarian cells. RNA-seq results showed that the PI3K-Akt pathway differentially changed. Kinotome analysis showed that WM03 specifically targeted 4 kinases of 50 curcumin-effective kinases and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) was the most significant kinase, The IC WM03 specifically targets DYRK2 and is more potent than curcumin to inhibit cisplatin resistant ovarian cancer cells, being a promising new drug candidate for ovarian cancers.