A range of natural products have been extensively studied for their chemopreventive potential for cancer, including those that inhibit growth and induce apoptosis. Sidr honey derived from the Ziziphus or Lote tree (Ziziphus spina-christi, Ziziphus lotus, or Ziziphus jujuba) is used in a wide range of traditional medicine practices. In the current study, the Saudi Sidr honey was analyzed by means of a GC–MS chromatogram and investigated for its antiproliferative effects on colorectal cancer cells (HCT-116), breast cancer cells (MCF-7), and lung cancer cells (A-549), as well as its apoptosis induction and cell cycle arrest potentials against human colorectal cancer cells (HCT-116). The effects of Saudi Sidr honey on cells were determined using the MTT assay and the clonogenic assay. The induction of apoptosis was studied using Annexin V-FITC flow cytometry analysis. The propidium iodide staining method was used to detect cell cycle arrest via flow cytometry. By means of performing GS–MS and HR-LCMS analysis, 23 different chemical components were identified from Saudi Sidr honey. A dose–response analysis showed that Saudi Sidr honey was more effective against HCT-116 (IC50 = 61.89 ± 1.89 µg/mL) than against MCF-7 (IC50 = 78.79 ± 1.37 µg/mL) and A-549 (IC50 = 94.99 ± 1.44 µg/mL). The antiproliferation activity of Saudi Sidr honey has been found to be linked to the aggregation of cells during the G1 phase, an increase in early and late apoptosis, and necrotic cell death in HCT-116 cells. Considering these promising findings that highlight the potential use of Saudi Sidr honey as an antitumor agent, further research should be carried out with the aim of isolating, characterizing, and evaluating the bioactive compounds involved in Sidr honey’s antiproliferative activity to better understand the mechanism of their action.
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