Turning an 'Achilles' Heel' into an asset--activation of HIF-1alpha during angiostatic therapy will increase tumor sensitivity to iron-catalyzed oxidative damage.
During angiostatic therapy, tumor hypoxia will activate the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), and will select for mutations which up-regulate the activity of this factor. This adaptation will increase tumor angiogenic capacity, while aiding the survival of poorly nourished cancer cells. A further effect of HIF-1alpha is to increase expression of transferrin receptors. The natural antimalarial drug artemisinin is selectively toxic to iron-loaded cells (such as malarial parasites), and it has recently been suggested that, inasmuch as many cancers overexpress transferrin receptors, such cancers might be treatable with a regimen comprised of iron supplementation and high-dose artemisinin. Thus, it can be anticipated that many tumors which evolve relative resistance to angiostatic therapy will be selectively susceptible to attack by the iron-loading/artemisinin strategy.
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron / Q000378:metabolism; D008962:Models, Theoretical; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
D020533:Angiogenesis Inhibitors; D037621:Artemisinins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011990:Receptors, Transferrin; D012717:Sesquiterpenes; D014157:Transcription Factors; C031327:artemisinin; D007501:Iron; D010100:Oxygen