科研之友
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摘要
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)
