This systematic review and meta-analysis was aimed to synthesize existing preclinical evidence on digoxin's anti-tumor effects via HIF-1α inhibition. This study was conducted as per PRISMA 2020 guidelines. A systematic literature search was conducted using PubMed/Medline, EMBASE, and Google Scholar, and based on the inclusion and exclusion criteria, a total of 13 studies were selected. The meta-analysis performed on the included studies revealed that the digoxin treatment decreased the tumor volume (IV:-1.40(-1.89 to -0.91) at 95% CI, p<0.00001, I 2 =42%), H I F-1α (IV:-2.43(-4.07 to -0.78) at 95% CI, p=0.004, I 2 = 62%), VEGF (IV:-1.14(-1.91 to -0.36) at 95% CI, p=0.004, I 2 = 0%), and GLUT-1 (IV: 1.57(-2.57 to -0.57) at 95% CI, p=0.002 I 2 = 0%), but had no statistically significant reduction in the tumor weight (IV:-0.31(-0.69 to 0.07), 95% CI, p=0.11, I 2 =98%), and CD31 marker (IV:-1.15(-3.10 to 0.79) at 95% CI, p=0.25, I 2 =71%) and has no effect on the animal survival rate (IV:6.46(-0.93 to 13.86) at 95% CI, p=0.09, I 2 =86%) compared to the control. Conclusions: In summary, the available moderate weight of evidence suggests that digoxin possesses potential anti-tumor effects via HIF-1α pathways. However, considering the pitfalls associated with the existing studies, there is a scope for conducting more robust pre-clinical studies. Further, randomized controlled trials in humans are essential to evaluate and validate the antitumor effect of digoxin. • Meta-analysis shows digoxin reduces tumor growth in preclinical models • Digoxin targets hypoxia inducible factor (HIF-1α) driving tumor growth pathways • Associated with reduced tumor size and key signals linked to growth • No consistent effect on survival or tumor weight across studies • Further preclinical studies and human trials are needed for validation
Bolar et al. (Sun,) studied this question.