Beta Caryophyllene in Combination with Dexmedetomidine Synergistically Inhibits Cell Proliferation in Ovarian Cancer: Involvement of AMPK and PGC-1α/TFAM

Ovarian cancer is a lethal malignancy with poor prognosis and low overall survival rate due to late diagnosis and asymptotic behaviour at early stages. The aim of this investigation was to evaluate the synergistic effect of β-Caryophyllene and dexmedetomidine on cell proliferation, apoptosis and tumor growth inhibition in ovarian cancer. Human ovarian epithelial cells were cultured with dexmedetomidine alone, β-Caryophyllene alone or β-Caryophyllene together with dexmedetomidine for 24 h and analyzed for cell proliferation with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Enzyme-linked immunoassay based kit was used to determine apoptotic deoxyribonucleic acid fragmentation. Western blotting was used to determine expression levels of target proteins. The induction of experimental human ovarian epithelial cells tumor in rat model was achieved through the injection of human ovarian epithelial tumor cells subcutaneously into the middle left side of the mice after anesthetization with pentobarbital (35 mg/kg) at 2.8×106 cells in 400 μl of phosphate buffered saline. We found that β-Caryophyllene and dexmedetomidine combination significantly enhances the anti-proliferative effects on human ovarian epithelial cells compared to individual treatments. Furthermore, β-Caryophyllene and dexmedetomidine combination significantly enhances apoptotic cell death compared to individual treatments. Furthermore, β-Caryophyllene and dexmedetomidine combination significantly causes up-regulation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and mitochondrial transcription factor A compared to individual treatments. Finally, we observed that β-Caryophyllene and dexmedetomidine combination significantly suppressed tumor growth in mice without changing body weight compared to individual treatments. β-Caryophyllene in combination with dexmedetomidine synergistically enhances anti-cancer effects in ovarian cancer through adenosine monophosphate-activated protein kinase activation and peroxisome proliferator-activated receptor-gamma coactivator-1α/mitochondrial transcription factor A over expression. The results point towards the potential combinational use of β-Caryophyllene and dexmedetomidine in ovarian cancer treatment.