Synergistic effect of bromocriptine and tumor necrosis factor-alpha on reversing hepatocellular carcinoma multidrug resistance in nude mouse MDR1 model of liver neoplasm.
OBJECTIVE
To investigate the effect of bromocriptine (BCT) and tumor necrosis factor-alpha (TNF-alpha) on hepatocellular carcinoma (HCC) multidrug resistance (MDR) in nude mouse MDR model of liver neoplasm.


METHODS
Human hepatocarcinoma cell line HepG(2), drug resistant hepatocarcinoma cell line HepG(2)/adriamycin (ADM) and hepatocarcinoma cell line transfected with TNF-alpha gene HepG(2)/ADM/TNF were injected into the liver of nude mice via orthotopic implantation and MDR model of liver neoplasm in vivo was established (HepG(2), ADM, TNF, BCT groups). Among these groups, BCT group and TNF group were treated with BCT through gastric canal. Each group was divided into control group and chemotherapy group. Size and weight of the tumor were measured. Furthermore, tumor histological character and growth of the nude mice were observed and their chemosensitivity was tested. MDR-associated genes and proteins (MRP, LRP) of implanted tumors were detected by immunohistochemistry, reverse transcriptase polymerase chain reaction, and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay.


RESULTS
The nude mouse model of each cell line was inoculated successfully. The tumor growth rate and weight were significantly different among groups. After chemotherapy, abdominal cavity tumor growth inhibition rate was higher in BCT group (67%) compared to ADM and TNF groups, and similar to HepG(2) group (54%). MDR1 and LRPmRNA could be detected in all groups, but TNF-alpha was detected only in TNF and BCT groups. Furthermore, MDR1 and LRP protein expression of tumors in TNF and BCT groups was low similar to HepG(2) group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups with TUNEL assay.


CONCLUSIONS
BCT and TNF-alpha can reverse HCC MDR in nude mouse MDR1 model of liver neoplasm.
Ding
Lei
L
Hepatic Surgery Center, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Chen
Xiao-Ping
XP
Zhang
Zhi-Wei
ZW
Guan
Jian
J
Zhang
Wan-Guang
WG
Wang
Hai-Ping
HP
Wang
Zhi-Hui
ZH
Li
Chun-Lei
CL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001971:Bromocriptine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001971:Bromocriptine