Human solid
tumors contain hypoxic regions that have considerably lower
oxygen tension than the normal tissues.
Hypoxia offers resistance to
radiotherapy and anticancer
chemotherapy, as well as predispose to increased
tumor metastases. Furthermore,
hypoxia induces
hypoxia-inducible factor-1 (HIF-1), which in turn increases
tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic
tumor cells is very important for
cancer therapy. We have previously reported that
procaspase-3 fused with a von Hippel-Lindau (VHL)-mediated
protein destruction motif of alpha subunit of HIF-1 (HIF-1alpha) containing Pro564, named TAT-ODD-procaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active
tumor cells. HIF-1 activity in the xenografts of human
tumor cells, which express
luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in
tumors was more rapidly increased by ionizing radiation (IR) compared to untreated
tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated
tumors as well as unirradiated ones, indicating TOP3 eradicated
tumor cells with HIF-1-activity induced by IR as well as
hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of
tumor xenografts. These results further strengthen the argument that HIF-1-active/hypoxic cells play crucial roles in angiogenesis and radioresistance.