Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma.

Abstract

New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or haematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation, while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homoeostasis in cancer cells can thus synergize with targeted agents to promote tumour regression in vivo.

• Authors: Ugur Eskiocak, Vijayashree Ramesh, Jennifer G Gill, Zhiyu Zhao, Stacy W Yuan, Meng Wang, Travis Vandergriff, Mark Shackleton, Elsa Quintana, Timothy M Johnson, Ralph J DeBerardinis, Sean J Morrison
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 12336 (08 22 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27545456 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Protein Kinase Inhibitors
• Digitoxin
• MAP Kinase Kinase 1
• ATP1A1 protein, human
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Cell Line, Tumor
• Digitoxin (pharmacology, therapeutic use)
• Drug Synergism
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Humans
• Hydrogen-Ion Concentration (drug effects)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• Male
• Melanocytes
• Melanoma (drug therapy, mortality, pathology)
• Mice
• Mitochondria (drug effects, metabolism)
• Mutation
• Phosphorylation
• Primary Cell Culture
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Skin (pathology)
• Skin Neoplasms (drug therapy, mortality, pathology)
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)
• Xenograft Model Antitumor Assays