Palonosetron, a 5-HT3 Receptor Antagonist, Induces G1 Cell Cycle Arrest and Autophagy in Gastric Cancer Cells

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Authors: Yoo, Young Chul ; Lin, Lin ; Lee, Sihak ; Shin, Yeeun Rachel ; Oh, Ju Eun ; Kim, Na Young

MeSH: Animals ; Autophagy* / drug effects ; Cell Line, Tumor ; Cell Movement / drug effects ; Cell Proliferation / drug effects ; G1 Phase Cell Cycle Checkpoints* / drug effects ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Palonosetron* / pharmacology ; Receptors, Serotonin, 5-HT3 / metabolism ; Serotonin 5-HT3 Receptor Antagonists* / pharmacology ; Stomach Neoplasms* / drug therapy ; Stomach Neoplasms* / metabolism ; Stomach Neoplasms* / pathology ; Xenograft Model Antitumor Assays

Abstract: Serotonin or 5-hydroxytryptamine (5-HT) has been implicated in promoting cancer cell growth by acting on 5-HT receptors, such as 5-HT1 and 5-HT2 receptors. However, the role of 5-HT3 receptor antagonists in gastric cancer cell lines remains unclear. This study aimed to evaluate the effect of 5-HT3 receptor antagonists (ondansetron, palonosetron, and ramosetron) on cancer cell growth using AGS and MKN-1 cell lines, as well as the xenograft mouse model. All the three antagonists inhibited cell proliferation, migration, and colony formation in AGS cells. Specifically, palonosetron induced G1 cell cycle arrest, autophagy, and phosphorylation of GSK3 beta, along with increased expression of p27, p53, and LC3B. In vivo studies demonstrated that palonosetron reduced tumor growth and modulated pro-inflammatory cytokines-tumor necrosis factor alpha, interleukin 6, and interleukin 1 beta. These findings suggest that 5-HT3 receptor antagonists, especially palonosetron, exert anti-tumor effects in gastric cancer through G1 cell cycle regulation and immunomodulation. The results position palonosetron as a promising lead for further preclinical development in gastric cancer.