Preclinical evidence for digoxin's anti-tumor activity through HIF-1α pathways: Systematic review and meta-analysis

Objectives: This systematic review and meta-analysis was aimed to synthesize existing preclinical evidence on digoxin's anti-tumor effects via HIF-1α inhibition. Methods: 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. Results: 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, I²= 42%), HIF-1α (IV:-2.43(-4.07 to −0.78) at 95% CI, p = 0.004, I² = 62%), VEGF (IV:-1.14(-1.91 to −0.36) at 95% CI, p = 0.004, I² = 0%), and GLUT-1 (IV: -1.57(-2.57 to −0.57) at 95% CI, p = 0.002 I² = 0%), but had no statistically significant reduction in the tumor weight (IV:-0.31(-0.69 to 0.07), 95% CI, p = 0.11, I²= 98%), and CD31 marker (IV:-1.15(-3.10 to 0.79) at 95% CI, p = 0.25, I²= 71%) and has no effect on the animal survival rate (IV:6.46(-0.93 to 13.86) at 95% CI, p = 0.09, I²= 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.