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Article: High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: Dual effects on cancer cell and angiogenesis

TitleHigh doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: Dual effects on cancer cell and angiogenesis
Authors
Issue Date2006
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
Citation
Molecular Cancer Therapeutics, 2006, v. 5 n. 9, p. 2261-2270 How to Cite?
AbstractThe present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC model, in which hypoxia was generated by hepatic artery ligation (HAL). Compared with HAL alone, PTK787 combined with HAL significantly prolonged the animal survival, reduced the tumor size, induced more tumor tissue necrosis and apoptosis, and down-regulated the expression of von Willebrand factor. The mechanism was explored in vitro using murine HCC and endothelial cell lines, respectively. PTK787 combined with hypoxia decreased the expression of VEGF and VEGF receptors in both cell lines and suppressed the cell viability by induction of cell cycle arrest and promotion of apoptosis. Up-regulation of cleaved form caspase-9 and down-regulation of Bcl-2 and cyclin D1 were detected with the combined treatment. Hypoxia sensitized endothelial cells to the inhibitory effect of PTK787 on forming tubular-like structure. The motility of tumor cells was inhibited by hypoxia and the combined approach, with down-regulation of Rac1, Rho, and phosphorylated Akt expression. However, in the endothelial cells, the combined treatment inhibited the hypoxia-enhanced cell motility, with suppressed Rac1, Rho, and phosphorylated Akt expression. In conclusion, PTK787 combined with hypoxia achieved a better therapeutic efficacy than hypoxia alone through enhancing hypoxia-induced antitumor cell effect and preventing the activation of angiogenic proces. Copyright © 2006 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/83202
ISSN
2015 Impact Factor: 5.579
2015 SCImago Journal Rankings: 3.224
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYang, ZFen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorLau, CKen_HK
dc.contributor.authorHo, DWen_HK
dc.contributor.authorTam, KHen_HK
dc.contributor.authorLam, CTen_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2010-09-06T08:38:13Z-
dc.date.available2010-09-06T08:38:13Z-
dc.date.issued2006en_HK
dc.identifier.citationMolecular Cancer Therapeutics, 2006, v. 5 n. 9, p. 2261-2270en_HK
dc.identifier.issn1535-7163en_HK
dc.identifier.urihttp://hdl.handle.net/10722/83202-
dc.description.abstractThe present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC model, in which hypoxia was generated by hepatic artery ligation (HAL). Compared with HAL alone, PTK787 combined with HAL significantly prolonged the animal survival, reduced the tumor size, induced more tumor tissue necrosis and apoptosis, and down-regulated the expression of von Willebrand factor. The mechanism was explored in vitro using murine HCC and endothelial cell lines, respectively. PTK787 combined with hypoxia decreased the expression of VEGF and VEGF receptors in both cell lines and suppressed the cell viability by induction of cell cycle arrest and promotion of apoptosis. Up-regulation of cleaved form caspase-9 and down-regulation of Bcl-2 and cyclin D1 were detected with the combined treatment. Hypoxia sensitized endothelial cells to the inhibitory effect of PTK787 on forming tubular-like structure. The motility of tumor cells was inhibited by hypoxia and the combined approach, with down-regulation of Rac1, Rho, and phosphorylated Akt expression. However, in the endothelial cells, the combined treatment inhibited the hypoxia-enhanced cell motility, with suppressed Rac1, Rho, and phosphorylated Akt expression. In conclusion, PTK787 combined with hypoxia achieved a better therapeutic efficacy than hypoxia alone through enhancing hypoxia-induced antitumor cell effect and preventing the activation of angiogenic proces. Copyright © 2006 American Association for Cancer Research.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/en_HK
dc.relation.ispartofMolecular Cancer Therapeuticsen_HK
dc.titleHigh doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: Dual effects on cancer cell and angiogenesisen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1535-7163&volume=5&issue=9&spage=2261&epage=2270&date=2006&atitle=High+doses+of+tyrosine+kinase+inhibitor+PTK787+enhance+the+efficacy+of+ischemic+hypoxia+for+the+treatment+of+hepatocellular+carcinoma:+dual+effects+on+cancer+cell+and+angiogenesisen_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1535-7163.MCT-06-0149en_HK
dc.identifier.pmid16985060-
dc.identifier.scopuseid_2-s2.0-33749565425en_HK
dc.identifier.hkuros124176en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33749565425&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume5en_HK
dc.identifier.issue9en_HK
dc.identifier.spage2261en_HK
dc.identifier.epage2270en_HK
dc.identifier.isiWOS:000240691800015-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYang, ZF=39863860200en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK
dc.identifier.scopusauthoridLiu, Y=14627533300en_HK
dc.identifier.scopusauthoridLau, CK=7401968442en_HK
dc.identifier.scopusauthoridHo, DW=7402971906en_HK
dc.identifier.scopusauthoridTam, KH=7201692833en_HK
dc.identifier.scopusauthoridLam, CT=7402989860en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK

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