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Preprint WatchModerateSeptember 20th, 2026

Na+/K+-ATPase Blockade Reversibly Attenuates Proliferation and Metabolic Function in K562 Human Myelogenous Leukemia Cells

Bowden, S. R.; Colton, E. T.; Norgaard, A. D.; Haas, M. M.; Dunnigan, E. R.; Goven, C. J.; Goven, G. O.; Hinnenkamp, T. J.; Walker, K. D.; Ballance, T. M.; Kathol, B. I.; Murphy, E. R.; Van Slyke, K. M.; Webb, R. J.; Biggane, E. R.; Biggane, J. P.

Pharmacological blockade of the Na+/K+-ATPase with digoxin attenuates proliferation and metabolic reducing capacity in K562 chronic myelogenous leukemia cells with an IC50 of 151.0 nM, an effect the authors attribute to on-target pump occupancy rather than scaffold-mediated signaling, and one that is cytostatic and fully reversible on drug clearance.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint argues that Na+/K+-ATPase occupancy by digoxin constrains leukemic cell growth through ion dyshomeostasis rather than through the pump's scaffolding role, and it reports a cytostatic, fully reversible effect at submicromolar concentrations. The single ATP1A1 failure on file runs in the opposite pharmacological direction. AMAG-423 in severe preeclampsia (amag-423-digoxin-immune-fab-severe-preeclampsia-dsmb-futility) was a digoxin immune Fab intended to neutralize endogenous cardiotonic steroids, and it stopped for futility at a data monitoring committee review, which is recorded here as an efficacy failure. Read together, the two say that the clinical evidence for modulating this pump in either direction is thin, and that a cell-line IC50 in a BCR-ABL positive, TP53-null, CDKN2A-deleted background is a long way from a human dependency. The result is reversible and cytostatic rather than cytotoxic, so it does not establish that ATP1A1 blockade would clear disease. Teams citing it as target validation should state which patient population they believe carries the dependency.

Abstract excerpt

The Na+/K+-ATPase consumes a substantial portion of cellular ATP to maintain essential electrochemical gradients, yet its role in regulating cancer cell proliferation and phenotypic plasticity remains complicated by its dual function as an ion transporter and a scaffolding receptor. Here, we investigate the physiological consequences of pharmacological NKA blockade using digoxin in K562 human chronic myelogenous leukemia cells. Submicromolar digoxin exposure induced a concentration-dependent attenuation of cell proliferation (IC50 = 151.0 nM) and a statistically significant depression of metabolic reducing capacity without impairing cell viability. Competitive supplementation with extracellular potassium salts produced a surmountable rightward shift in digoxin sensitivity, confirming that growth inhibition is driven by on-target NKA pump occupancy rather than non-specific interactions. Furthermore, this cytostatic growth attenuation and metabolic depression were found to be fully reversible upon drug clearance. K562 cells are largely refractory to canonical kinase-overdrive stress checkpoints as they harbor constitutive BCR-ABL tyrosine kinase activity alongside non-functional TP53 and a homozygous deletion of CDKN2A (p16INK4a). Consequently, these findings suggest that NKA perturbation attenuates K562 growth primarily through ion dyshomeostasis and secondary active transport constraints rather than scaffold-mediated signaling. Overall, we present a novel model for elucidating the role of the NKA in cancer proliferation and dissecting the mechanistic underpinnings of ion-mediated alterations in cancer cell physiology.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.