IA-0130, a novel 3-(1,3-diarylallylidene)oxindole derivative, alleviates ovarian cancer via inhibiting IL-6/gp130/STAT3 signalling

Background and Purpose: Dysregulation of the IL-6/glycoprotein 130(gp130)/STAT3 signalling axis is implicated in several human diseases, particularly cancer. Notably, gp130, a single transducer of this signalling axis, is a target for ovarian cancer treatment. However, data regarding small-molecule inhibitors of gp130 are lacking. Therefore, we aimed to identify a 3-(1,3-diarylallylidene)oxindole derivative that binds gp130 and reveal the anticancer mechanism acting on the IL-6/gp130/STAT3 pathway in ovarian cancer. Experimental Approach: We synthesised 24 derivatives based on the scaffold of 3-(1,3-diarylallylidene)oxindole, and derivatives that inhibit IL-6 signalling were selected using HEK-Blue™ IL-6 cells. The binding of derivatives to gp130 was assessed using surface plasmon resonance. IA-0130, with a strong gp130-binding ability, was selected to observe its effect on the migration, invasion, cell cycle arrest and apoptosis of ovarian cancer cells in comparison to bazedoxifene, a known gp130-binding derivative. Additionally, we examined the mechanism underlying the tumour suppressive effect of IA-0130 in vivo. Key Results: We found that IA-0130 inhibited gp130/STAT3 phosphorylation in a concentration-dependent manner in ovarian cancer cell line and also in ovarian cancer-resistant cell line. By suppressing the expression of downstream target genes, IA-0130 inhibited cancer cell growth, metastasis, and invasion and induced apoptosis, exhibiting anticancer effects. In a mouse xenograft model of human ovarian cancer, oral administration of IA-0130 significantly delayed tumour growth. Conclusions and Implications. IA-0130 inhibits tumour growth, migration and metastasis by inhibiting IL-6/gp130/STAT3 signalling in ovarian cancer by binding gp130. IA-0130 holds therapeutic potential for treating ovarian cancer as well as anticancer drug-resistant ovarian cancer.