title: Caffeic acid derivatives inhibit the growth of colon cancer: involvement of the PI3-K/Akt and AMPK signaling pathways.
abstract: BACKGROUND
  The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated.
  
  
  RESULTS
  CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G0/G1 cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells.
  
  
  CONCLUSIONS
  CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells.
authors: Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China; NCHU-UCD Plant and Food Biotechnology Program and Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.
authors: En-Pei Isabel
authors: EP
authors: Chiang
authors: Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China.
authors: Shu-Yao
authors: SY
authors: Tsai
authors: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan, Republic of China; Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China.
authors: Yueh-Hsiung
authors: YH
authors: Kuo
authors: Department of Anatomy, Taipei Medical University, Taipei, Taiwan, Republic of China.
authors: Man-Hui
authors: MH
authors: Pai
authors: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan, Republic of China; Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China.
authors: Hsi-Lin
authors: HL
authors: Chiu
authors: Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America.
authors: Raymond L
authors: RL
authors: Rodriguez
authors: Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan, Republic of China.
authors: Feng-Yao
authors: FY
authors: Tang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002109:Caffeic Acids / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C000602374:3-phenylpropyl caffeate; D000970:Antineoplastic Agents; D002109:Caffeic Acids; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol