Moracin D Inhibits Gastric Cancer Progression Through B-Cell Lymphoma-2 (Bcl-2)-Mediated Cell Cycle Arrest and Apoptosis, Enhancing Chemotherapy Efficacy

Gastric cancer (GC) is a highly prevalent and rapidly progressing cancer with a poor prognosis, primarily due to chemoresistance and treatment-related toxicity. Moracin D (MD), a benzofuran extracted from <i>Morus alba</i> L., has shown potential antitumor effects in various malignancies, although its impact on GC remains limited. The aim of this study was to assess the anticancer potential of MD in human gastric cancer cell lines and subcutaneous xenograft models. We examined cell proliferation, clonogenic ability, cell cycle progression, and apoptosis using MTT, BrdU, colony formation assays, flow cytometry, Western blotting, and immunohistochemistry. Our findings suggest that MD selectively inhibited GC cell proliferation and reduced DNA synthesis in vitro. It also inhibited colony formation and tumor growth in vivo, affecting GC cell clonogenicity without affecting body weight or vital organs, and without overt toxicity under the experimental conditions tested. Mechanistically, MD was found to induce G₂/M cell-cycle arrest, potentially through modulation of cyclin B1 and CDK1, and to trigger apoptosis in GC cells, which may involve the mitochondrial pathway as suggested by changes in Bcl-2 and pro-apoptotic protein levels. While Bcl-2 overexpression partially reversed MD-induced inhibition of proliferation and apoptosis, further studies are required to confirm its role as a mediator. Additionally, MD enhances the anticancer effects of 5-fluorouracil (5-FU) through synergistic mechanism. This study highlights the observed antiproliferative and proapoptotic effects of MD in preclinical models and suggests its potential as monotherapy or in combination with 5-FU as a promising therapeutic approach in the treatment of gastric cancer.