Digoxin Downregulates NDRG1 and VEGF through the Inhibition of HIF-1α under Hypoxic Conditions in Human Lung Adenocarcinoma A549 Cells

Abstract

Digoxin, an inhibitor of Na+/K+ ATPase, has been used in the treatment of heart-related diseases (such as congestive heart failure and atrial arrhythmia) for decades. Recently, it was reported that digoxin is also an effective HIF-1α inhibitor. We investigated whether digoxin could suppress tumor cell growth through HIF-1α in non-small cell lung cancer cells (A549 cells) under hypoxic conditions. An MTT assay was used to measure cell viability. RT-PCR and western blotting were performed to analyze the mRNA and protein expression of VEGF, NDRG1, and HIF-1α. HIF-1α nuclear translocation was then determined by EMSA. Digoxin was found to inhibit the proliferation of A549 cells under hypoxic conditions. Our results showed that hypoxia led to the upregulation of VEGF, NDRG1, and HIF-1α both at the mRNA and protein levels. We also found that the hypoxia-induced overexpression of VEGF, NDRG1, and HIF-1α was suppressed by digoxin in a concentration-dependent manner. As expected, our EMSA results demonstrated that under hypoxic conditions HIF-1α nuclear translocation was also markedly reduced by digoxin in a concentration-dependent manner. Our results suggest that digoxin downregulated hypoxia-induced overexpression of VEGF and NDRG1 at the transcriptional level probably through the inhibition of HIF-1α synthesis in A549 cells.

Upregulation of extrinsic apoptotic pathway in curcumin‐mediated antiproliferative effect on human pancreatic carcinogenesis

“…The protein encoded by this gene is a cytoplasmic protein involved in stress responses, hormone responses, cell growth, and differentiation [Ellen et al, ]. A recent study reported that digoxin inhibited tumor cell growth through down‐regulation of NDRG1 [Wei et al, ]. Our gene expression results provide clear evidence that NDRG1 was among significantly down‐regulated genes in both cell lines after curcumin treatment suggesting that NDRG1 inhibition plays a role in the chemopreventive effect of curcumin on pancreatic cancer cells.…”

Hypoxia-Inducible Factors and Cancer

“…Interestingly, several other identified drugs were also cardiac glycosides [115, 116]. Digoxin inhibited HIF-1α and VEGF in non-small cell lung cancer cells cultured in hypoxia, reducing their viability [117, 118]. In a retrospective analysis, patients with prostate cancer taking a non-specific HIF-1α inhibitor such as digoxin, metformin or angiotensin-2 receptor blocker exhibited a lower risk of prostate cancer progression [119].…”

Targeting Na+/K+‐translocating adenosine triphosphatase in cancer treatment

“…Meanwhile, oleandrin has shown antiproliferative properties in lung cancer by activating the TNF‐related apoptosis‐inducing ligand‐mediated apoptotic pathway . Cardiac glycosides appear to induce the autophagy of NSCLC cells by inhibiting HIF1 α , mTOR, and ERK1/2 …”