Antisense hypoxia-inducible factor 1alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma

Cancer Sci. 2008 Oct;99(10):2055-61. doi: 10.1111/j.1349-7006.2008.00905.x.


Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is resistant to anticancer drugs. Hypoxia is a major cause of tumor resistance to chemotherapy, and hypoxia-inducible factor (HIF)-1 is a key transcription factor in hypoxic responses. We have previously demonstrated that gene transfer of an antisense HIF-1alpha expression vector downregulates expression of HIF-1alpha and vascular endothelial growth factor (VEGF), and synergizes with immunotherapy to eradicate lymphomas. The aim of the present study was to determine whether gene transfer of antisense HIF-1alpha could enhance the therapeutic efficacy of doxorubicin to combat HCC. Both antisense HIF-1alpha therapy and doxorubicin suppressed the growth of subcutaneous human HepG2 tumors established in BALB/c nude mice, tumor angiogenesis, and cell proliferation, and induced tumor cell apoptosis. The combination therapy with antisense HIF-1alpha and doxorubicin was more effective in suppressing tumor growth, angiogenesis, and cell proliferation, and inducing cell apoptosis than the respective monotherapies. Gene transfer of antisense HIF-1alpha downregulated the expression of both HIF-1alpha and VEGF, whereas doxorubicin only downregulated VEGF expression. Antisense HIF-1alpha and doxorubicin synergized to downregulate VEGF expression. Both antisense HIF-1alpha and doxorubicin inhibited expression of proliferating cell nuclear antigen, and combined to exert even stronger inhibition of proliferating cell nuclear antigen expression. Antisense HIF-1alpha therapy warrants investigation as a therapeutic strategy to enhance the efficacy of doxorubicin for treating HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Antisense Elements (Genetics) / genetics
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / drug therapy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Doxorubicin / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / therapeutic use*
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Liver Neoplasms, Experimental / blood supply
  • Liver Neoplasms, Experimental / prevention & control*
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy
  • Proliferating Cell Nuclear Antigen / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays


  • Antibiotics, Antineoplastic
  • Antisense Elements (Genetics)
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen
  • Vascular Endothelial Growth Factor A
  • Doxorubicin