Unveiling the antitumor and chemo-sensitizing effects of ondansetron in the treatment of MCF-7 breast cancer cells

Abstract Breast cancer (BC) remains one of the global leading causes of cancer-related deaths among women. Resistance to chemotherapy and metastatic progression are key challenges. Serotonin (5-HT) and its receptor subtypes are implicated in tumor proliferation, but the oncogenic role of 5-HT3-Rs in BC is not well defined. The widely-used antiemetic, Ondansetron , is a selective 5-HT3 receptor antagonist, that is investigated in this study to explore the potential previously-unrecognized anticancer properties in MCF-7 human BC cells. To investigate the potential effect of Ondansetron , alone or in combination with Doxorubicin , in inhibiting proliferation, survival and migration of MCF-7 BC cells, and to explore some of the underlying molecular mechanisms. MCF-7 cells were treated with Ondansetron and/or Doxorubicin . Cell viability- (MTT), migration- (wound healing), and survival- (clonogenic) assays were conducted. The regulation of some downstream signaling pathways were analyzed by ELISA, Western blotting, or immunofluorescence to assess the modulations of migratory/metastatic (RAS/mTOR/SRC/FAK/MMP-2), survival/angiogenic (Cyclin D1/VEGF-A), and apoptotic ( Bcl-2/Cytochrome c/cleaved-caspase-7 ) biomarkers. Ondansetron significantly reduced cell viability and migration capability and markedly potentiated the cytotoxic effects of Doxorubicin . The combination regimen, downregulated key oncogenic signaling molecules ( RAS/mTOR/SRC/FAK/MMP-2/VEGF-A/Cyclin D1 ) with enhanced Cytochrome c / cleaved-caspase-7 activation, and suppressed the anti-apoptotic protein, Bcl-2. Pharmacological targeting of 5-HT/HTR3 with Ondansetron induces antitumor effects in MCF-7 BC cells by suppressing 5-HT3-mediated survival signaling and metastatic pathways, and increases MCF-7 cells sensitivity to chemotherapy. This study proposes using Ondansetron as a potential adjuvant to Doxorubicin -based treatment of BC, to improve efficacy and reduce toxicity of the chemotherapy.