Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth

Abstract

A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 M. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1␣ protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1␣ by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy.cancer therapy ͉ hypoxia ͉ tumor xenograft

Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia

“…Increasing the perfusion pressure from 0.1 to 2.5 Pa was sufficient to remove BMDACs bound to HUVECs cultured at 20% O 2 but not at 1% O 2 , which is consistent with the known activation of vascular endothelium in ischemic tissue. To determine whether the effect of DMOG was HIF-1-dependent, BMDACs were cultured in the presence of DMOG and digoxin, which inhibits HIF-1␣ and HIF-2␣ protein synthesis (31). Digoxin blocked the effect of DMOG on BMDAC adhesion to hypoxic endothelium (Fig.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…Digoxin and other members of this class were shown to inhibit HIF-1α protein synthesis and expression of HIF-1α target genes in several cancer cells [172]. However, the mechanism by which these effects are mediated remains unclear.…”

“…However, the mechanism by which these effects are mediated remains unclear. It was suggested that cardiac glycosides promote sequestration of HIF-1α mRNA in stress granules [172], which are usually formed following exposure of cancer cells to hypoxia and contain mRNAs which are not translated until the cells are reoxygenated [173].…”

“…As discussed in detail in section 2.1., in mice bearing breast cancer orthografts, digoxin was reported to block lymphangiogenesis and lymphatic metastases to a similar extent as PDGFRβ inhibition by imatinib [36]. Interestingly, xenografts derived from cells with HIF-1α enforced expression were resistant to the anti-tumor effect of digoxin, showing that HIF-1α is the critical target of digoxin for cancer therapy [172]. Currently, digoxin is evaluated in a phase 2 clinical trial intended for newly diagnosed operable breast cancer [174].…”

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

“…Cardiac glycosides, including digoxin, have been found to decrease HIF-1α protein expression via inhibition of HIF-1α mRNA translation. 156 Acriflavine, which historically was used as a topical antiseptic, also inhibited HIF-1 function, though via a different mechanism: it inhibits dimerization of HIF-1α with HIF-1β, thus preventing formation of a functional HIF-1 unit. 157 Both medications have been found to have beneficial effects on PH in animal models.…”