Evaluating the specific STAT3 inhibitor YHO-1701 in ovarian cancer cell lines and patient-derived cell models: efficacy, mechanisms, and therapeutic potential
- Author:
Sho SATO
1
;
Takahito MIURA
;
Aiko OGASAWARA
;
Daisuke SHINTANI
;
Shogo YAMAGUCHI
;
Hiroaki INUI
;
Akiko YOSHINAGA
;
Masahiko NISHIYAMA
;
Momomi TSUGANE
;
Kosei HASEGAWA
Author Information
- Publication Type:Original Article
- From:Journal of Gynecologic Oncology 2025;36(2):e24-
- CountryRepublic of Korea
- Language:English
-
Abstract:
Objective:Signal transducer and activator of transcription 3 (STAT3) plays key roles in regulating cancer cell proliferation, survival, and metastasis. We aimed to determine the effects of YHO-1701, an oral STAT3 inhibitor, in ovarian cancer (OC).
Methods:We evaluated the impact of YHO-1701 on cell growth in patient-derived cells (PDCs) and OC cell lines using standard cell proliferation assays. Spheroid models derived from PDCs were assessed using three-dimensional (3D) cell viability assays. Antitumor activity was performed in SKOV3 xenograft mice treated orally administrated YHO-1701 with 20 mg/kg.Changes in STAT3 signaling were analyzed by western blotting. The molecular mechanisms of STAT3 inhibition were investigated by sequencing RNA and analyzing pathways in the SKOV3 using a small interfering RNA targeting STAT3 (STAT3 siRNA) and YHO-1701.
Results:YHO-1701 inhibited the growth of OC cell lines by preventing STAT3 dimerization and decreasing the expression of its downstream signaling molecule, survivin. The growth of PDCs and spheroids obtained from patients with primary and recurrent OCs was significantly inhibited. Antitumor effect was observed in the SKOV3 xenograft mice with YHO-1701. YHO-1701 induced apoptosis in OC cells. Additionally, p53 and/or MAPK signaling pathways were upregulated in SKOV3 cells incubated with YHO-1701 and in those with STAT3 siRNA.
Conclusion:Our results showed that YHO-1701 suppressed cell growth in PDCs of OC, accompanied by survivin inhibition, and a decrease in the number of peritoneal metastasis in the mice by YHO-1701, compared with those treated with control. Therefore, YHO-1701 could be a promising candidate agent for treating OC
