Inhibitor of signal transducer and activator of transcription 3 (STAT3) suppresses ovarian cancer growth, migration and invasion and enhances the effect of cisplatin in vitro

Abstract

ABSTRACT. The aim of the present study was to investigate the antiovarian cancer effect of the inhibitor of signal transducer and activator of transcription 3 (STAT3), WP1066. Western blot was used to detect the phosphorylation of STAT3 in ovarian cancer cell line SKOV3 and cisplatin-resistant ovarian cancer cell line SKOV3/DDP. MTT and colony-forming assays were performed to evaluate the viability and growth of ovarian cancer cells. The apoptosis of ovarian cancer cells was determined by flow cytometry. The wound healing assay and Transwell assay were performed to examine the migration and invasion of ovarian cancer cells. WP1066 significantly inhibited the phosphorylation of STAT3 in SKOV3 and SKOV3/DDP cells. WP1066 treatment inhibited the proliferation and clonogenicity of both SKOV3 and SKOV3/DDP cells. After WP1066 treatment for 24 h, the apoptosis rates of SKOV3 and SKOV3/DDP cells were significantly increased compared with the control cells. After treatment with WP1066, the reduction of the wound gaps was significantly less in both SKOV3 and Anti-ovarian cancer effect of WP1066 SKOV3/DDP cells. WP1066 also significantly inhibited the invasion capacity of SKOV3 and SKOV3/DDP cells compared with the control group. Treatment with WP1066 combined with cisplatin significantly increased proliferation inhibition and apoptosis in SKOV3 and SKOV3/ DDP cells compared with treatment with cisplatin alone. A synergistic action between WP1066 and cisplatin on the proliferation and apoptosis of ovarian cancer cells was determined. In conclusion, inhibition of STAT3 may suppress the proliferation, migration and invasion, induce apoptosis and enhance the chemosensitivity of ovarian cancer cells, indicating that STAT3 is a new therapeutic target of ovarian cancer.

Patient-derived ovarian cancer xenografts re-growing after a cisplatinum treatment are less responsive to a second drug re-challenge: a new experimental setting to study response to therapy

“…Its inhibition has been shown to have antitumor activity, and to reverse the sensitivity to therapy in different cancer types [28–30], including ovarian cancer [31, 32]. Recently, a STAT3 role in DDP resistance and acquisition of stem-like features by STAT3 activation has also been described [33].…”

Multiple regulation pathways and pivotal biological functions of STAT3 in cancer

“…For instance, ALD518, a humanized anti-IL-6 antibody, helps NSCLC patients obtain therapeutic benefits against cachexia, anemia, and drug resistance 89 . WP1066, a JAK2 inhibitor, suppresses ovarian cancer growth, migration, and invasion; this inhibitor also enhances the chemosensitivity of ovarian cancer cells and decreases the rate of STAT3 phosphorylation 90 . Direct inhibitors directly block the SH2, DNA-binding, and N-terminal domains of STAT3 to suppress protein dimerization, to inhibit DNA binding, and to prevent nuclear translocation, respectively.…”

Proteasome Inhibitor YSY01A Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant Human Ovarian Cancer Cells

“…Chemoresistance has previously been found to associate with the failure of cisplatin to induce apoptosis 22 . Numerous studies have demonstrated great contribution of NF-κB and STAT3 to cisplatin resistance via suppression of cisplatin-induced apoptosis 28 - 31 . The activation level of NF-κB is higher in cisplatin-resistant human epidermoid carcinoma cells and curcumin, an inhibitor of NF-κB activation, sensitizes the cisplatin-resistant cells by down-regulation of apoptosis-related proteins such as Bcl-2 28 .…”