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Conference Paper: Antitumor effect of tyrosine kinase inhibitor, AMN107, in hepatocellular carcinoma

TitleAntitumor effect of tyrosine kinase inhibitor, AMN107, in hepatocellular carcinoma
Authors
Issue Date2007
PublisherAmerican Association for Cancer Research
Citation
AACR 98th Annual Meeting, Los Angeles, CA, 14–18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 3244 How to Cite?
AbstractHepatocellular Carcinoma (HCC) is one of the most common malignancies and is responsible for more than one million deaths worldwide. In Hong Kong, it is the second leading cause of cancer death. Surgical resection or liver transplantation is the treatment of choice when HCC is diagnosed at an early stage. However, around 70% of patients are inoperable because of advanced tumor growth or severe underlying cirrhosis. Targeted therapy could be one of the main options for HCC patients. AMN107 is a novel and potent inhibitor of the protein tyrosine kinase activities of Bcr-Abl, c-kit and PDGFR. In the previous studies, the antitumor activity of AMN107 was attributed mainly to the treatment of chronic myeloid leukemia by targeting Bcr-Abl, and a direct antitumor effect in solid tumor was rarely reported. In this study, we investigated direct effect of AMN107 in nude mice bearing human HCC xenograft. Tumor tissues from a HCC nude mice established by human HCC cell lines were implanted orthotopically in the liver of nude mice. The in vitro effect of AMN107 on proliferation and apoptosis of human HCC cell lines was studied by MTT assay, flow cytometry and Western blot. Our results demonstrated that AMN107 oral administration to mice at 50mg/kg/day resulted in a significant reduction in tumor growth of HCC xenografts in nude mice. AMN107 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis in vitro. Furthermore, AMN107 downregulated bcl-xL expression in HCC cells. In addition, it is also found that PDGF could induced phosphorylation of ERK in HCC cell lines. The simulated effect by PDGF could be blocked by AMN107. In conclusion, this study demonstrated that AMN107 is potent inhibitors of tumor growth in HCC. The inhibition of tumor volumne by AMN107 may through direct effects on inhibition of tumor cell proliferation, induction of tumor cell apoptosis and blocking bcl-xL expression. AMN107 also inhibited the PDGF induced activation of ERK. Our data suggest that AMN107 may provide an effective therapy for human HCC.
Persistent Identifierhttp://hdl.handle.net/10722/108493
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorLui, ELHen_HK
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2010-09-26T00:41:57Z-
dc.date.available2010-09-26T00:41:57Z-
dc.date.issued2007en_HK
dc.identifier.citationAACR 98th Annual Meeting, Los Angeles, CA, 14–18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 3244-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/108493-
dc.description.abstractHepatocellular Carcinoma (HCC) is one of the most common malignancies and is responsible for more than one million deaths worldwide. In Hong Kong, it is the second leading cause of cancer death. Surgical resection or liver transplantation is the treatment of choice when HCC is diagnosed at an early stage. However, around 70% of patients are inoperable because of advanced tumor growth or severe underlying cirrhosis. Targeted therapy could be one of the main options for HCC patients. AMN107 is a novel and potent inhibitor of the protein tyrosine kinase activities of Bcr-Abl, c-kit and PDGFR. In the previous studies, the antitumor activity of AMN107 was attributed mainly to the treatment of chronic myeloid leukemia by targeting Bcr-Abl, and a direct antitumor effect in solid tumor was rarely reported. In this study, we investigated direct effect of AMN107 in nude mice bearing human HCC xenograft. Tumor tissues from a HCC nude mice established by human HCC cell lines were implanted orthotopically in the liver of nude mice. The in vitro effect of AMN107 on proliferation and apoptosis of human HCC cell lines was studied by MTT assay, flow cytometry and Western blot. Our results demonstrated that AMN107 oral administration to mice at 50mg/kg/day resulted in a significant reduction in tumor growth of HCC xenografts in nude mice. AMN107 inhibited tumor cell proliferation in a dose-dependent manner and also induced tumor cells to undergo apoptosis in vitro. Furthermore, AMN107 downregulated bcl-xL expression in HCC cells. In addition, it is also found that PDGF could induced phosphorylation of ERK in HCC cell lines. The simulated effect by PDGF could be blocked by AMN107. In conclusion, this study demonstrated that AMN107 is potent inhibitors of tumor growth in HCC. The inhibition of tumor volumne by AMN107 may through direct effects on inhibition of tumor cell proliferation, induction of tumor cell apoptosis and blocking bcl-xL expression. AMN107 also inhibited the PDGF induced activation of ERK. Our data suggest that AMN107 may provide an effective therapy for human HCC.-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Researchen_HK
dc.titleAntitumor effect of tyrosine kinase inhibitor, AMN107, in hepatocellular carcinomaen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailLui, ELH: h0148841@graduate.hku.hken_HK
dc.identifier.emailLiu, Y: ayliu@hkucc.hku.hken_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.identifier.hkuros140995en_HK

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