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Conference Paper: HIF-1a blockade enhances the therapeutic efficacy of hypoxia for the treatment of hepatocellular carcinoma (HCC)

TitleHIF-1a blockade enhances the therapeutic efficacy of hypoxia for the treatment of hepatocellular carcinoma (HCC)
Authors
Issue Date2006
PublisherKluwer Academic Publishers
Citation
The 2nd European Conference on Tumor Angiogenesis and Antiangiogenic Therapy (ECTA), Munich, Germany, 14-16 September 2006. In Angiogenesis, 2006, v. 9 n. S1, p. 28 Abstract no. P29 How to Cite?
AbstractBackground and objective: Transarterial embolization (TAE) is the major alternative for the treatment of non-resectable HCC. Although the hypoxic condition generated by hepatic artery blockade could induce tumor cell death, hypoxia-related angiogenesis and subsequent tumor re-growth might lead to treatment failure. Therefore, we designed the present study to investigate whether suppression of the activity of HIF- 1a, a key player in angiogenesis, could enhance the therapeutic efficacy of hypoxia. Materials and methods: In vivo, an orthotopic HCC model was generated by injection of tumor cells into the left lobe of the rat liver. Hypoxia was induced by hepatic artery ligation (HAL). YC-1, an anti-HIF-1a agent, was administered through intra-tumor injection right after hepatic artery ligation. Survival time was recorded and the histology of tumor tissue was studied. In vitro, hypoxia was induced by culturing the cells with 0.1% O2. YC-1 was administered to the tumor cells at different concentrations under hypoxic condition. The proliferation and death of the cells were determined by MTT assay and Annexin-V labeling, respectively. Molecular mechanism related to HIF-1a was determined by Western blot. Results: HAL stimulated HIF-1a upregulation in the tumor tissue with a peak level at 24 h. Administration of YC-1 significantly prolonged the survival of tumor-bearing rats. Both HAL and HAL combined with YC-1 induced tumor tissue necrosis. YC-1 administration decreased the number of HIF-1a+ cells in the tumor tissue. In the HCC tumor cells, YC-1 administration decreased the viability of tumor cells but did not cause any change in the number of apoptotic cells. Hypoxia upregulated the expression of HIF- 1a, that could be suppressed by YC-1 administration. In addition, YC-1 could inhibit HIF-1a expression despite the presence or absence of p53 in the tumor cell lines. However, the suppressive effect of YC-1 on HIF- 1a could be blocked by the transfection of MDM2, a downstream molecule of p53. Conclusion: The present study revealed that blockade of HIF-1a-related pathway could enhance the efficacy of hypoxia for the treatment of HCC. YC-1 achieved anti-HIF-1a effects through p53 independent and MDM2 dependent pathways.
Persistent Identifierhttp://hdl.handle.net/10722/108558
ISSN
2015 Impact Factor: 4.301
2015 SCImago Journal Rankings: 2.212

 

DC FieldValueLanguage
dc.contributor.authorLau, CKen_HK
dc.contributor.authorYang, Zen_HK
dc.contributor.authorNgai, PPen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2010-09-26T00:44:40Z-
dc.date.available2010-09-26T00:44:40Z-
dc.date.issued2006en_HK
dc.identifier.citationThe 2nd European Conference on Tumor Angiogenesis and Antiangiogenic Therapy (ECTA), Munich, Germany, 14-16 September 2006. In Angiogenesis, 2006, v. 9 n. S1, p. 28 Abstract no. P29-
dc.identifier.issn0969-6970-
dc.identifier.urihttp://hdl.handle.net/10722/108558-
dc.description.abstractBackground and objective: Transarterial embolization (TAE) is the major alternative for the treatment of non-resectable HCC. Although the hypoxic condition generated by hepatic artery blockade could induce tumor cell death, hypoxia-related angiogenesis and subsequent tumor re-growth might lead to treatment failure. Therefore, we designed the present study to investigate whether suppression of the activity of HIF- 1a, a key player in angiogenesis, could enhance the therapeutic efficacy of hypoxia. Materials and methods: In vivo, an orthotopic HCC model was generated by injection of tumor cells into the left lobe of the rat liver. Hypoxia was induced by hepatic artery ligation (HAL). YC-1, an anti-HIF-1a agent, was administered through intra-tumor injection right after hepatic artery ligation. Survival time was recorded and the histology of tumor tissue was studied. In vitro, hypoxia was induced by culturing the cells with 0.1% O2. YC-1 was administered to the tumor cells at different concentrations under hypoxic condition. The proliferation and death of the cells were determined by MTT assay and Annexin-V labeling, respectively. Molecular mechanism related to HIF-1a was determined by Western blot. Results: HAL stimulated HIF-1a upregulation in the tumor tissue with a peak level at 24 h. Administration of YC-1 significantly prolonged the survival of tumor-bearing rats. Both HAL and HAL combined with YC-1 induced tumor tissue necrosis. YC-1 administration decreased the number of HIF-1a+ cells in the tumor tissue. In the HCC tumor cells, YC-1 administration decreased the viability of tumor cells but did not cause any change in the number of apoptotic cells. Hypoxia upregulated the expression of HIF- 1a, that could be suppressed by YC-1 administration. In addition, YC-1 could inhibit HIF-1a expression despite the presence or absence of p53 in the tumor cell lines. However, the suppressive effect of YC-1 on HIF- 1a could be blocked by the transfection of MDM2, a downstream molecule of p53. Conclusion: The present study revealed that blockade of HIF-1a-related pathway could enhance the efficacy of hypoxia for the treatment of HCC. YC-1 achieved anti-HIF-1a effects through p53 independent and MDM2 dependent pathways.-
dc.languageengen_HK
dc.publisherKluwer Academic Publishers-
dc.relation.ispartofAngiogenesisen_HK
dc.titleHIF-1a blockade enhances the therapeutic efficacy of hypoxia for the treatment of hepatocellular carcinoma (HCC)en_HK
dc.typeConference_Paperen_HK
dc.identifier.emailLau, CK: lauck@HKUCC-COM.hku.hken_HK
dc.identifier.emailYang, Z: zfyang@hkucc.hku.hken_HK
dc.identifier.emailNgai, PP: ppngai@hotmail.comen_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.doi10.1007/s10456-006-9043-z-
dc.identifier.hkuros145459en_HK
dc.identifier.hkuros128501-

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