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

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-1 alpha expression vector downregulates expression of HIF-1 alpha 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-1 alpha could enhance the therapeutic efficacy of doxorubicin to combat HCC. Both antisense HIF-1 alpha 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-1 alpha 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-1 alpha downregulated the expression of both HIF-1 alpha and VEGF, whereas doxorubicin only downregulated VEGF expression. Antisense HIF-1 alpha and doxorubicin synergized to downregulate VEGF expression. Both antisense HIF-1 alpha and doxorubicin inhibited expression of proliferating cell nuclear antigen, and combined to exert even stronger inhibition of proliferating cell nuclear antigen expression. Antisense HIF-1 alpha therapy warrants investigation as a therapeutic strategy to enhance the efficacy of doxorubicin for treating HCC. (Cancer Sci 2008; 99: 2055-2061)