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

Ugur Eskiocak, Vijayashree Ramesh, Jennifer G. Gill, Zhiyu Zhao, Stacy W. Yuan, Meng Wang, Travis Vandergriff, Mark Shackleton, Elsa Quintana, Arthur E. Frankel, Timothy M. Johnson, Ralph J. DeBerardinis and Sean J. Morrison ()
Additional contact information
Ugur Eskiocak: Children’s Research Institute
Vijayashree Ramesh: Children’s Research Institute
Jennifer G. Gill: Children’s Research Institute
Zhiyu Zhao: Children’s Research Institute
Stacy W. Yuan: Children’s Research Institute
Meng Wang: Children’s Research Institute
Travis Vandergriff: University of Texas Southwestern Medical Center
Mark Shackleton: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre
Elsa Quintana: Life Sciences Institute, University of Michigan
Arthur E. Frankel: Simmons Cancer Center, University of Texas Southwestern Medical Center
Timothy M. Johnson: University of Michigan
Ralph J. DeBerardinis: Children’s Research Institute
Sean J. Morrison: Children’s Research Institute

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12336

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