Abstract
Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.
Highlights
Solid tumor tissues often contain hypoxic regions, in which the supply of oxygen and nutrition is reduced because of an immature vascular network, and in which there is rapid tumor progression [1]
These results indicate that human cancer cells are maintained under hypoxic conditions in the hypoxia chamber
Adenovirus-based oncolytic virotherapy has recently emerged as a promising antitumor therapy, a hypoxic microenvironment has been shown to reduce the replication of wild-type adenovirus in target tumor cells [26,27]
Summary
Solid tumor tissues often contain hypoxic regions, in which the supply of oxygen and nutrition is reduced because of an immature vascular network, and in which there is rapid tumor progression [1]. Recent accumulated evidence suggests that hypoxia induces cancer progression-related characteristics such as epithelial-mesenchymal transition (EMT) [6,7] and stemness properties [8,9,10,11] of tumor cells. Acquisition of such properties by tumor cells within hypoxic areas of tumor tissues would greatly contribute to tumor progression and recurrence. Tumor-specific antitumor activity of OBP-301 against various types of human cancer cells with high telomerase activity has been demonstrated in both in vitro and in vivo settings [14,18,19]. Whether OBP-301 has an antitumor effect against hypoxic tumor cells remains unclear
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