Extended O6-methylguanine methyltransferase promoter hypermethylation following n-butylidenephthalide combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on inhibition of human hepatocellular carcinoma cell growth.
Epigenetic alteration of DNA methylation plays an important role in the regulation of gene expression associated with chemosensitivity of human hepatocellular (HCC) carcinoma cells. With the aim of improving the chemotherapeutic efficacy for HCC, the effect of the naturally occurring compound n-butylidenephthalide (BP), which is isolated from a chloroform extract of Angelica sinensis, was investigated. In both HepG2 and J5 HCC cell lines, a synergistic antiproliferative effect was observed when a low dosage of BP was combined with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is an alkylating agent, and it prompts us to examine one of DNA repair genes, O(6)-methylguanine methyltransferase (MGMT). It was evident from methylation-specific polymerase chain reaction (PCR) analysis that BP/BCNU combined treatment caused a time- and concentration-dependent enhancement of MGMT promoter methylation. Overexpression of MGMT could abolish BP-induced growth inhibition in the J5 tumor cell line as measured by colony formation assay. When BP was combined with BCNU and administered, it showed significant antitumor effects in both HepG2 and J5 xenograft tumors as compared with the use of only one of these drugs. The BCNU-induced apoptosis and inhibited MGMT protein expression in HCC cells, both in vitro and in vivo, resulting from the combination treatment of BP and BCNU suggest a potential clinical use of this compound for improving the prognosis for HCCs.
Yu
Yung-Luen
YL
Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University and Hospital, Taichung, Taiwan.
Yu
Sung-Liang
SL
Su
Kuo-Jung
KJ
Wei
Chyou-Wei
CW
Jian
Min-Hui
MH
Lin
Po-Cheng
PC
Tseng
I-Hsuan
IH
Lin
Chai-Ching
CC
Su
Chin-Cheng
CC
Chan
De-Chuan
DC
Lin
Shinn-Zong
SZ
Harn
Horng-Jyh
HJ
Chen
Yi-Lin Sophia
YL
D029971:Angelica sinensis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D002330:Carmustine / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D010796:Phthalic Anhydrides / Q000008:administration & dosage*; D010936:Plant Extracts / Q000008:administration & dosage
D000970:Antineoplastic Agents; D010796:Phthalic Anhydrides; D010936:Plant Extracts; D019853:O(6)-Methylguanine-DNA Methyltransferase; C026105:butylidenephthalide; D002330:Carmustine