title: Melatonin potentiates the antiproliferative and pro-apoptotic effects of ursolic acid in colon cancer cells by modulating multiple signaling pathways.
abstract: Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is largely distributed in medical herbs and edible plants. Melatonin is an indoleamine compound produced in the pineal gland and also a plant-derived product. Both UA and melatonin have been shown to inhibit cancer cell growth in numerous studies, but they have never been combined altogether as an anticolon cancer treatment. In this study, we investigated whether the association between UA and melatonin leads to an enhanced antiproliferative and pro-apoptotic activities in colon cancer SW480 and LoVo cells. We found that combined treatment with UA and melatonin significantly enhanced inhibition of cell viability and migration, promoted changes in cell morphology and spreading, and increased induction of apoptosis, thereby potentiating the effects of UA alone in colon cancer cells. Moreover, we found that the enhanced effects of UA and melatonin combination are mediated through simultaneous modulation of cytochrome c/caspase, MMP9/COX-2, and p300/NF-κB signaling pathways. Combined treatment with UA and melatonin triggered the release of cytochrome c from the mitochondrial intermembrane space into the cytosol, induced cleavage of caspase and PARP proteins, enhanced inhibition of MMP9 and COX-2 expression, promoted p300 and NF-κB translocation from cell nuclei to cytoplasm, and abrogated NF-κB binding and p300 recruitment to COX-2 promoter in colon cancer cells. These results, therefore, demonstrated that melatonin potentiated the antiproliferative and pro-apoptotic effects of UA in colon cancer cells by modulating multiple signaling pathways and suggest that such a combinational treatment might potentially become an effective way in colon cancer therapy.
authors: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors: Jingshu
authors: J
authors: Wang
authors: Wei
authors: W
authors: Guo
authors: Wangbing
authors: W
authors: Chen
authors: Wendan
authors: W
authors: Yu
authors: Yun
authors: Y
authors: Tian
authors: Lingyi
authors: L
authors: Fu
authors: Dingbo
authors: D
authors: Shi
authors: Bing
authors: B
authors: Tong
authors: Xiangsheng
authors: X
authors: Xiao
authors: Wenlin
authors: W
authors: Huang
authors: Wuguo
authors: W
authors: Deng
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017931:DNA Primers; D008550:Melatonin
keywords: COX‐2; NF‐κB; caspase; colon cancer; cytochrome c; melatonin; p300; ursolic acid