Propolis cinnamic acid derivatives induce apoptosis through both extrinsic and intrinsic apoptosis signaling pathways and modulate of miRNA expression.
Propolis cinnamic acid derivatives have a number of biological activities including anti-oxidant and anti-cancer ones. In this study, we aimed to elucidate the mechanism of the anti-cancer activity of 3 representative propolis cinnamic acid derivatives, i.e., Artepilin C, Baccharin and Drupanin in human colon cancer cell lines. Our study demonstrated that these compounds had a potent apoptosis-inductive effect even on drug-resistant colon cancer cells. Combination treatment of human colon cancer DLD-1 cells with 2 of these compounds, each at its IC20 concentration, induced apoptosis by stimulating both intrinsic and extrinsic apoptosis signaling pathways. Especially, Baccharin plus Drupanin exhibited a synergistic growth-inhibitory effect by strengthening both intrinsic and extrinsic apoptotic signaling transduction through TRAIL/DR4/5 and/or FasL/Fas death-signaling loops and by increasing the expression level of miR-143, resulting in decreased expression levels of the target gene MAPK/Erk5 and its downstream target c-Myc. These data suggest that the supplemental intake of these compounds found in propolis has enormous significance with respect to cancer prevention.
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Graduate School of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Minami
M
Kumazaki
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Haruka
H
Shinohara
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Kohei
K
Taniguchi
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Nami
N
Yamada
Nagaragawa Research Center, API Co., Ltd., Nagara, Gifu, Japan.
Shozo
S
Ohta
Nagaragawa Research Center, API Co., Ltd., Nagara, Gifu, Japan.
Kenji
K
Ichihara
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: yakao@gifu-u.ac.jp.
Yukihiro
Y
Akao
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008519:Medicine, Traditional; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010666:Phenylpropionates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011429:Propolis / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D014255:Trichothecenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D002934:Cinnamates; C000596937:Drupanin; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D010666:Phenylpropionates; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014255:Trichothecenes; D000077150:Oxaliplatin; C029010:cinnamic acid; C102259:artepillin C; D011429:Propolis; C012764:baccharin; D005472:Fluorouracil
Apoptosis; Phytochemicals; Propolis cinnamic acid derivatives; TNF family; miR-143