ARC-111, a small-molecule
topoisomerase I inhibitor, is a potent cytotoxic drug against multiple human
cancer cell lines under normoxic conditions (Li et al.,
Cancer Res 2003; 63:8400-8407). In this study, we explore the potential of
ARC-111 as a
hypoxia-inducible factor-1alpha inhibitor under hypoxic conditions. The
transcription factor,
hypoxia-inducible factor-1alpha, is an essential regulator of
tumorigenesis and an attractive molecular target for
cancer therapy. We demonstrate that
ARC-111 specifically inhibits
hypoxia-induced accumulation of
hypoxia-inducible factor-1alpha, but not other short half-life
proteins in multiple human
cancer cell lines.
ARC-111 inhibits
hypoxia-inducible factor-1alpha
protein synthesis specifically and does not inhibit
protein synthesis globally. We demonstrate that inhibition of
hypoxia-inducible factor-1alpha accumulation by
ARC-111 is independent of proteasomal degradation. In addition, we demonstrate using
topoisomerase I-resistant cell lines that
topoisomerase I is required for ARC-111-mediated
hypoxia-inducible factor-1alpha inhibition. Experiments performed with
nocodazole indicate that
ARC-111 inhibits
hypoxia-inducible factor-1alpha accumulation in a cell-cycle-independent manner. Analysis of AKT and
mammalian target of rapamycin phosphorylation reveals that
ARC-111 does not exhibit inhibitory effect on the phosphatidylinositol-3-kinase AKT
mammalian target of rapamycin signaling pathway. It has been previously shown that
topotecan, a
topoisomerase I inhibitor, can also modulate
hypoxia-induced
hypoxia-inducible factor-1alpha accumulation (Rapisarda et al.,
Cancer Res 2003; 64:1475-1482). In addition to inhibiting
hypoxia-induced accumulation of
hypoxia-inducible factor-1alpha,
ARC-111 exhibits antiproliferative effects against multiple human
cancer cell lines. We demonstrate that
topoisomerase I is required for the antiproliferative effects of
ARC-111. Antiproliferative effects of
ARC-111, however, are
oxygen-independent, which is distinguishable from inhibition of
hypoxia-inducible factor-1alpha accumulation by
ARC-111, which is only observed under
hypoxia. The results indicate that inhibiting
hypoxia-inducible factor-1alpha accumulation and exhibiting antiproliferation of
ARC-111 are through distinct mechanisms of action, which reinforce the potential anticancer effect of
ARC-111 on hypoxic
tumors.