Hypoxia is a characteristic feature of advanced solid
tumors and may worsen prognosis. The development of
tumor-targeted and
hypoxia-inducible gene therapy vectors holds promise to selectively deliver and express suicidal or cytotoxic genes in hypoxic regions of
tumors. In this regard, the promoter of the
survivin gene, which encodes an
anti-apoptotic protein that is strongly expressed in
tumor tissue, has received attention because of its supposed inducibility by
hypoxia. However, in our present study we demonstrate that treatment of various tumor cell lines with chronic
hypoxia or with the
hypoxia-mimetic
CoCl(2) does not result in increased expression of
survivin, but rather strongly suppresses this gene's activity. In contrast, expression of
glucose-regulated
protein 78 (
GRP78/Bip) is substantially elevated under chronic
hypoxia in vitro and in hypoxic areas of
tumor tissue in vivo. Although
tumor cells in general exhibit increased chemoresistance under hypoxic conditions, we found that hypoxic
glioblastoma cells are more sensitive to killing by the selective
cyclooxygenase-2 (COX-2) inhibitor
celecoxib, and this effect is reflected by further decreased expression of
survivin. Intriguingly,
2,5-dimethyl-celecoxib (DMC), a close structural analog of
celecoxib that lacks the ability to inhibit COX-2, is able to potently mimic the anti-
tumor effects of its parent compound, indicating that inhibition of COX-2 is not involved in these processes. Taken together, our results caution against the use of
survivin-based promoters to target hypoxic areas of
tumors, but favor constructs that include the strongly
hypoxia-inducible
GRP78 promoter. In addition, our data introduce
celecoxib as a
drug with increased cytotoxicity against hypoxic
tumor cells.