[Antitumor and anti-angiogenic effects of manumycin on human hepatocellular carcinoma HepG2 xenografts in nude mice].
OBJECTIVE
Farnesyl-transferase inhibitor manumycin has in vitro and in vivo antitumor effects on pancreatic cancer, colon cancer, and anaplastic thyroid carcinoma. Our previous experiments showed that manumycin could inhibit proliferation pathway and survival pathway in human hepatocellular carcinoma HepG2 cells in vitro. This study was to examine the antitumor and anti-angiogenic effects of manumycin on HepG2 xenografts in nude mice.


METHODS
The xenografts derived from HepG2 cells were established in BALB/C nude mice. Inoculated mice were randomly divided into normal saline (NS) group, positive control (cyclophosphamide, CTX, 25 mg/kg) group, negative control (0.1% Me2SO, 20 ml/kg) group, low dose munumycin (2.5 mg/kg) group, and high dose munumycin (5 mg/kg) group. Tumor volume was measured in nude mice bearing xenografts. Microvessel density (MVD) was observed by immunohistochemistry. Protein levels of vascular endothelial growth factor (VEGF) and b-fibroblast growth factor (b-FGF) were determined by Western blot; mRNA level of VEGF was analyzed using reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
The mean tumor volume ratio of nude mice xenograft (V/V(0)) was significantly lower in low dose manumycin group and high dose manumycin group than in negative control group (0.68+/-0.09 and 0.59+/-0.04 vs. 1.38+/-0.21, P < 0.01). MVD was significantly lower in manumycin-treated groups than in control group (P < 0.01). Manumycin significantly down-regulated protein level of VEGF in HepG2 cells and HepG2 xenografts, and mRNA level of VEGF in HepG2 xenografts, but didn't affect protein level of b-FGF.


CONCLUSIONS
Manumycin could inhibit the growth of human hepatocellular carcinoma HepG2 xenografts in nude mice. The down-regulation of VEGF expression and the inhibition of angiogenesis might play a key role in the anti-neoplastic effect of manumycin.
Zhou
Jun-Min
JM
Skate Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Zhu
Xiao-Feng
XF
Liu
Zong-Chao
ZC
Fu
Li-Wu
LW
Yang
Xiao-Ping
XP
Liang
Yong-Ju
YJ
Pan
Qi-Chao
QC
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011090:Polyenes / Q000008:administration & dosage / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C054474:manumycin