β-Caryophyllene Induces PPARγ-Mediated Apoptosis and Enhances the Radiosensitivity in Colorectal Cancer Cells

Purpose: This study aimed to investigate the radiosensitizing potential of β-caryophyllene (BCP), a natural CB2 receptor agonist, in colorectal cancer (CRC) cells and to elucidate the underlying molecular mechanisms. Methods: Murine CT26 and human HCT116 CRC cells were treated with BCP alone or in combination with radiotherapy (RT). Cell viability was evaluated using the MTT assay, and combination index (CI) values were calculated to assess synergy. Flow cytometry and immunofluorescence were used to analyze cell cycle distribution and DNA damage. Protein expression levels of PPARγ, phosphorylated AKT (pAKT), cyclin D1, Bax, Bcl-2, and cleaved caspase-3 were examined by western blot. Results: BCP synergistically enhanced RT-induced cytotoxicity in both CRC cell lines, with CI values ranging from 0.92 to 0.70 in CT26 cells and from 0.78 to 0.68 in HCT116 cells at 4 and 8 Gy irradiation. The combination treatment resulted in significant G2/M arrest and sustained γH2AX expression at both 24 and 48 h, indicating persistent DNA double-strand breaks. BCP suppressed pAKT and cyclin D1 levels while upregulated PPARγ expression. Activated apoptosis was verified by increased Bax/Bcl-2 ratios and elevated cleaved caspase-3 levels. Conclusion: BCP enhances the radiosensitivity of CRC cells by promoting RT-induced DNA damage and triggering PPARγ-mediated apoptotic pathways. These findings support its potential as a natural radiosensitizer in CRC treatment.