Inhibitory effect of LZJ541, a novel small molecule inhibitor of STAT3, on the proliferation of hepatocellular carcinoma cells / 药学学报

Signal transducer and activator of transcription 3 (STAT3) is an important regulatory factor of cell proliferation and metastasis, involved in the occurrence and development of a variety of malignant tumors, and it is one of the hot spots in the research of targeted anti-tumor drugs. Our group screened a novel benzobis (imidazole) structure small molecule compound LZJ541 through the screening model of Janus kinase (JAK)/STAT3 pathway inhibitors, which has definite STAT3 inhibitory activity. We examined the effect of LZJ541 on the proliferation of HepG2 and PC-3 cells by MTT assay in vitro, detected the effect of LZJ541 on the expression of STAT3-related proteins in HepG2 cells by Western blot, and measured the effect of LZJ541 on the apoptosis and cell cycle arrest of HepG2 cells via flow cytometry. The results indicated that LZJ541 significantly inhibited the activation of STAT3 signaling pathway and restrained the proliferation of HepG2 cells. Its half maximal inhibitory concentration (IC50) was 13.8 μmol·L-1, which was much lower than that of PC-3 cells (with low STAT3 expression, IC50: 41.99 μmol·L-1), LZJ541 can also inhibit the phosphorylation of STAT3 in HepG2 cells, thereby inducing apoptosis and cycle arrest and then exerting anti-tumor effects. In conclusion, LZJ541 has a certain anti-tumor effect in vitro, which provides an experimental basis for the development of new STAT3-targeted anti-tumor drugs around this kind of compounds.

Inhibition of STAT3 signaling induces apoptosis and suppresses growth of lung cancer: good and bad / 한국실험동물학회지

Signal transducer and activator of transcription 3 (STAT3) modulates a variety of genes involved in the regulation of critical functions, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, and immunity. For many cancers, elevated levels of STAT3 signaling have been associated with a poor prognosis and the development of chemotherapy resistance. In this study, we investigated the inhibitory effects of a novel small-molecule inhibitor of STAT3, STX-0119, on the cell viability and survival of human lung cancer cells. STX-0119 inhibited activated STAT3 and the expression of STAT3-regulated oncoproteins such as c-Myc, cyclin D1, and survivin in lung cancer cells. STX-0119 also decreased the amount of STAT3 in the nuclear fraction as well as induced apoptosis of these lung cancer cell lines as evidenced by increases in apoptotic cells (Annexin V positive) and poly (ADP-ribose) polymerase (PARP) cleavage. The efficacy of STX-0119 in a mouse xenograft model was confirmed. However, a hematological side effect, which had not been previously reported, was observed. The level of white blood cells was significantly lowered when treated at the dose at which STX-0119 alone showed a significant tumor-suppressive effect. In conclusion, we suggest that STX-0119 may be a potent therapeutic agent against lung cancer. Consideration of the side effect suggests, it is necessary to study whether low-dose STX-0119 is effective for lung treatment with a combination of classic lung cancer therapeutics.

Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. RESULTS: Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression. CONCLUSION: This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.