bp-1-102 and Stomach-Neoplasms

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of many human cancers and has been widely recognized as a promising target for cancer therapy. A variety of small-molecule inhibitors have been developed for targeting STAT3, and some of them are now undergoing clinical trials. S3I-201, a known STAT3 inhibitor, may block STAT3 function in cancer cells by binding to the STAT3 SH2 domain to disrupt STAT3 protein complex formation. Using S3I-201 as a starting point for drug development, we synthesized a series of new STAT3 inhibitors 9a-x in this study by introducing naphthoquinone unit, a privileged fragment in STAT3 inhibitors. Most of the compounds exhibited strong anti-proliferation activity of gastric cancer cells (MGC803, MKN28, MNK1, and AGS). The representative compound 9n (SIL-14) could effectively inhibit the colony formation and migration of gastric cancer cells MGC803, arrest the cell cycle and induce MGC803 cell apoptosis at low micromolar concentrations in vitro. In addition, SIL-14 can also inhibit the phosphorylation of STAT3 protein and significantly decrease the expression of total STAT3, suggesting that it may exert anticancer effects by blocking the STAT3 signaling pathway. These results support that SIL-14 may be a promising STAT3 inhibitor for the further development of potential anti-gastric cancer candidates.

Topics: Aminosalicylic Acids; Benzenesulfonates; Cell Line, Tumor; Cell Proliferation; Humans; Naphthoquinones; STAT3 Transcription Factor; Stomach Neoplasms

BP‑1‑102, a novel inhibitor of signal transducer and activator of transcription 3 (STAT3), exhibits significant antitumor effects in several malignancies in vitro and in vivo. However, its role in gastric cancer (GC) remains to be elucidated. In the present study, the effect and potential molecular mechanisms of BP‑102 in human GC cell lines were investigated. The results showed that BP‑1‑02 dose‑dependently inhibited the proliferation of AGS cells, whereas it had little effect on HGC‑27 cells. Flow cytometric analysis indicated that BP‑1‑102 induced apoptosis, but had minimal effect on cell cycle distribution. In addition, cells treated with BP‑1‑102 demonstrated markedly suppressed migration and invasion capacities. Western blot analysis revealed that BP‑1‑102 inhibited the phosphorylation of STAT3 and its target genes, including c‑Myc, cyclin D1 and survivin, in a time‑ and dose‑dependent manner. Furthermore, it was found that BP‑1‑102 induced the phosphorylation of c‑Jun N‑terminal kinase and p38 mitogen‑activated protein kinase (MAPK) and inhibited the activation of extracellular signal‑related kinases. Taken together, these results demonstrated that BP‑1‑102 may be a potent antitumor agent that acts through modulating the STAT3 and MAPK signaling pathways in GC cells.

Topics: Aminosalicylic Acids; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Humans; Mitogen-Activated Protein Kinases; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Sulfonamides