Berberine counteracts enhanced IL-8 expression of AGS cells induced by evodiamine.
OBJECTIVE
Although showing an anti-tumor activity, evodiamine also up-regulated IL-8 production of human gastric cancer AGS cells. This study aimed to assess this effect and to examine whether co-administration with berberine counteracts it.


METHODS
MTT assay was used to assess the cell proliferation and adhesive ability. Flow cytometry was performed to measure the cell cycle distribution. Wound healing assay was used to detect the migration ability of cells. IL-8 production was determined by ELISA. Levels of mRNA expression of IL-8, VCAM-1 and ICAM-1 were measured by real-time PCR. Molecular pathways involved were evaluated by ELISA and western-blotting methods.


RESULTS
Evodiamine triggered proliferative inhibition and cell cycle arrest, and decreased migration of AGS cells. IL-8 expression and the adhesive ability of AGS cells to HUVECs were significantly increased by evodiamine, but were inhibited after being co-treated with berberine in AGS cells. As IL-8 was neutralized, increased adhesion of AGS cells to HUVECs induced by evodiamine was abolished. Berberine significantly suppressed the up-regulation of VCAM-1 and the down-regulation of ICAM-1 induced by evodiamine. Evodiamine provoked IL-8 secretion via ERK1/2, SAPK/JNK, JAK2 and AP-1 pathways which could be counteracted by berberine.


CONCLUSIONS
Although showing anti-proliferative and anti-migratory activities in AGS cells, evodiamine displayed a potential tendency to promote metastasis of gastric cancer cells by increasing IL-8 secretion and adhesion molecules. However, berberine could counteract the side-effect and simultaneously keep anti-proliferative and anti-migratory properties of evodiamine on AGS cells, which reduces the risk to use evodiamine in therapy of gastric cancers.
Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Zhangjiang Hi-tech Park, Shanghai 201203, China; Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, XuHui District, Shanghai 200032, China.
Hai-Lian
HL
Shi
Xiao-Jun
XJ
Wu
Yan
Y
Liu
Jian-Qun
JQ
Xie
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001599:Berberine / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000235:genetics; D019743:Chemokines, CXC; D002867:Chromones / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; C508524:CXCL17 protein, human; D018925:Chemokines; D019743:Chemokines, CXC; D002867:Chromones; C573420:ICAM1 protein, human; D007093:Imidazoles; D016209:Interleukin-8; D009025:Morpholines; D011725:Pyridines; D011799:Quinazolines; D001599:Berberine; D018799:Intercellular Adhesion Molecule-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C049639:evodiamine; C093642:SB 203580
AGS cells; Adhesion; Berberine; Evodiamine; IL-8