Abstract
Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1α (HIF-1α) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1α expression by decreasing HIF-1α protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1α is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1α is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers.
Highlights
Hepatocellular carcinoma is the most frequently occurring primary liver cancer, with an incidence of half a million cases per year worldwide [1]
hypoxia-inducible factor 1a (HIF-1a) protein level is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma cell lines
The IC50s for SN-38, TPT, HCPT, and MONCPT were similar under 0.6% O2 for Bel-7402/HIF-1a (-), hypoxia-induced resistance disappeared in HIF-1a gene silencing cells (Fig. 1B and Supplementary Fig. S1)
Summary
Hepatocellular carcinoma is the most frequently occurring primary liver cancer, with an incidence of half a million cases per year worldwide [1]. We and other groups [3, 4] have found that the expression of HIF-1a is increased in most hepatocellular carcinomas and is associated with poor. Because fibrogenesis during the development of cirrhosis destroys the normal blood supply to the liver, the blood supply is limited in hepatocellular carcinoma with cirrhosis, which leads to local hypoxia [5]. Hypoxia leads to the activation of hypoxia-inducible factor 1a (HIF-1a), which acts as the transcriptional factor for a variety of essential genes in the hypoxic microenvironment, including those encoding for VEGF and basic fibroblast growth factor [6–8]
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