Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent

Abstract

Gliomas are the most common primary brain tumors with a usually fatal malignancy. They are associated with a poor prognosis although multiple therapeutic options have been available. Trimebutine is one of the prokinetic agents and it has been mainly used for treatment of disorders of the gastrointestinal (GI) tract such as irritable bowel syndrome. However, its effects on glioma cells remain unknown. Here, we used various concentrations of trimebutine to treat SHG44, U251, and U-87 MG human glioma/glioblastoma cells. And combined experiments of MTT, colony formation assay, and wound healing assay, as well as western blot and immunofluorescence staining were used to evaluate the effects of trimebutine on glioma cells. The results demonstrated that trimebutine significantly inhibited cell viability and colony formation. A significant inhibition of glioma cell migration was also indicated by wound healing assay. In addition, trimebutine promoted cell apoptosis and induced Bcl-2 downregulation, accompanied with Bax upregulation. Both immunofluorescence staining and western blot results showed that trimebutine increased the level of active Caspase-3. Moreover, trimebutine reduced the activation of both AKT and ERK signaling pathways. In subcutaneous U-87 MG cell xenograft tumors in nude mice, trimebutine significantly inhibited tumor growth. More TUNEL-positive apoptotic cells in tumor sections were observed in trimebutine-treated mice when compared to the vehicle control. Reduced Bcl-2 and upregulated Bax, as well as perturbed p-AKT and p-ERK signaling pathways were also observed in trimebutine-treated xenograft tissues. Our combined data indicated that trimebutine may be potentially applied for the clinical management of glioma/glioblastoma.

β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling

“…Bax is a member of the Bcl-2 protein family related to apoptosis. The ratio of pro- and anti-apoptotic molecules modulates apoptosis (Knudson and Korsmeyer, 1997; Fan et al, 2018). The results illustrated that the combination treatment significantly downregulated Bcl-2 levels but upregulated Bax levels (Figures 7D,E).…”

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells

“…Our data also showed that opioid receptor expression in ovarian CSCs was not high and that opioid receptor agonists, such as DAMGO and dynorphin, had no effect, thereby demonstrating TM did not act through the opioid receptor in ovarian CSCs. It was also reported that TM acts as an opioid receptor agonist in glioma and glioblastoma cells, and inhibits cell proliferation at a range of 50–400µM without difference between glioma and glioblastoma cells by inhibiting ERK and AKT signaling pathways [ 41 ]. On the other hand, our data showed that TM could act on ovarian CSCs more selectively and effectively by the inhibition of stemness-related transcription factors, such as OCT3/4 and SOX2, through a blockade of the calcium and BKCa channels that are overexpressed in the ovarian CSCs.…”

Trimebutine Maleate Monotherapy for Functional Dyspepsia: A Multicenter, Randomized, Double-Blind Placebo Controlled Prospective Trial

“…Regarding preclinical studies, TM was recently shown to be effective at maintaining upper and lower GI motor function in a peripheral CRF overlapping model with guinea pigs [ 33 ]. It is worth noting that apart from GI tract motility disorders, recent data suggest that TM may exert antitumor activities against gut and brain malignancies [ 34 ].…”