Suppression of tumor growth using antisense oligonucleotide against survivin in an orthotopic transplant model of human hepatocellular carcinoma in nude mice.
Survivin, an inhibitor of apoptosis protein, deserves attention as a selective target for cancer therapy because it is overexpressed in many cancers, including human hepatocellular carcinoma (HCC). Here, we report a novel antisense oligonucleotide (ASO) against survivin for its effectiveness against tumor growth both in vitro and in vivo, and providing evidence in treatment for HCC. Initially, transfection of liver tumor cells HepG2 with ASO resulted in significant cells growth inhibition and reduction expression of survivin mRNA and protein, in a dose-dependent manner. Using caspase-3 protease activation assays, we observed that ASO has induced significantly greater apoptosis rate compared to control oligonucleotides. Furthermore, we used an orthotopic transplant model of HCC in nude mice to investigate the effect of ASO on tumor growth in vivo, and ASO reagents were delivered by intravenous injection. Interestingly, this systemic treatment also resulted in significant inhibition in tumor growth. Tumor growth in mice treated with ASO (50 and 75 mg/kg per day) was significantly inhibited (45.31% and 60.94%, respectively) compared with saline-injected group (p < 0.01), in a dose-dependent manner, and the effect of ASO on tumor growth was associated with downregulation of survivin in tumor xenografts. Moreover, the level of serum alpha-fetoprotein in ASO-treated groups was also decreased in a dose-dependent manner. Taken together, these data suggest that the usefulness of survivin ASO could potentially be a promising gene therapy approach to treatment of HCC.
Sun
Yuning
Y
Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
Lin
Ruxian
R
Dai
Jinming
J
Jin
Dazhi
D
Wang
Sheng-qi
SQ
D000818:Animals; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D014162:Transfection; D014183:Transplantation, Heterologous
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077022:Survivin; D053148:Caspase 3