A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins.
OBJECTIVE
A major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), has previously been shown to induce cell-cycle arrest and apoptosis in various cancers. However, little is known about its effects on hepatocellular carcinomas (HCCs).


METHODS
Four HCC cell lines, HLE, HepG2, HuH-7 and PLC/PRF/5, were treated with EGCG or vehicle. Cell viability was assessed by trypan blue staining and WST-8 assay. Cell-cycle, apoptosis and apoptosis-related proteins in HLE cells were evaluated by flow cytometry and Western blotting. The effect of EGCG was also studied in vivo using a xenograft model. The effect of co-treatment with EGCG and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was also assessed.


RESULTS
EGCG inhibited the growth of all HCC cell lines at concentrations of 50-100 microg/ml. In HLE cells, EGCG induced apoptosis but not cell-cycle arrest and appears to have down-regulated Bcl-2alpha and Bcl-xl by inactivation of NF-kappaB. Oral administration of EGCG showed similar effects in HLE xenograft tumors. Co-treatment with EGCG and TRAIL synergistically induced apoptosis in HLE cells.


CONCLUSIONS
EGCG induced apoptosis in HLE cells, both in vitro and in vivo. Moreover, it enhanced TRAIL-induced apoptosis. Therefore, EGCG treatment may be useful for improving the prognosis of HCCs.
Nishikawa
T
T
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. liverresearch2004@yahoo.co.jp
Nakajima
T
T
Moriguchi
M
M
Jo
M
M
Sekoguchi
S
S
Ishii
M
M
Takashima
H
H
Katagishi
T
T
Kimura
H
H
Minami
M
M
Itoh
Y
Y
Kagawa
K
K
Okanoue
T
T
D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000032:analysis / Q000627:therapeutic use*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000627:therapeutic use; D028241:Camellia sinensis / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013662:Tea / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013662:Tea; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002392:Catechin; C045651:epigallocatechin gallate; D020169:Caspases