[HIF-1alpha determines sensitivity of endothelial cells to Bortezomib]
>>Blood. 2006 Nov 16; [Epub ahead of print]
Hypoxia-inducible transcription factor-1alpha determines sensitivity of endothelial cells to the proteosome inhibitor Bortezomib.
Veschini L, Belloni D, Foglieni C, Cangi MG, Ferrarini M, Caligaris-Cappio F, Ferrero E.
IRCCS H San Raffaele, Italy.
Angiogenesis is a complex, orchestrated process that plays a critical role in several conditions and has special relevance in the progression of cancer. Hypoxia is the major stimulus for angiogenesis, and HIF-1alpha is its key mediator. We set up a novel in vitro model of HIF-1alpha upregulation by treating HUVEC with the hypoxia mimicking Deferoxamine (DFO) and found that this condition was sufficient to promote angiogenesis, like the well-known HUVEC model cultured under low pO2. The proteasome inhibitor Bortezomib, which induces strong apoptosis in cancer cells, abrogated proliferation and angiogenesis of HUVEC when used at high concentration (100 nM) yet promoted both functions at low dosage (10 nM). This double-edged effect appeared to be mediated by differential effects exerted by the different concentrations of Bortezomib on two master regulators of tumor-associated angiogenesis, HIF-1alpha and NF-kB. Significantly, when HUVEC were induced to express HIF-1alpha prior to Bortezomib treatment, proliferative and angiogenic responses were abolished and a greatly enhanced proapoptotic effect was promoted with both concentrations of the drug. These findings indicate that HIF-1alpha upregulation may sensitize endothelial cells to the antiangiogenic and proapoptotic effects of Bortezomib and might be exploited to target tumor-associated vessels in the course of antiangiogenic therapies.<<
In contrast to most dogma, this asserts that upregulation of HIF-1alpha is a GOOD thing. Others are working on inhibiting it. Evidence seems to be accumulating that you can not only find potentially effective treatments by inhibiting something specific to the tumor that is necessary for its survival, but that one can also do so by making tumor cells overexpress such a target. Then the target seems to glom onto other things, gumming up the metabolic machinery, and thus causing apoptosis (possible clinical problem with this approach versus inhibition of the target: wouldn't this cause worse tumor lysis syndrome than we already see with Velcade alone?). So much for theory. I don't know how easy it might be upregulate HIF-1alpha specifically in human tumor cells in vivo. Interferon type 1 does it, but could it do so at acceptable doses? Adenosine does it, too, but it generally accumulates in hypoxic areas, not just those of tumor cells.
So rambling to the final question: Does anyone think upregulation of HIF-1alpha is a viable target?
Cheers, Tuck |
