The Na(+) /K(+) -translocating
adenosine triphosphatase (
ATPase) transports
sodium and
potassium across the plasma membrane and represents a potential target in
cancer chemotherapy. Na(+) /K(+) -
ATPase belongs to the
P-type ATPase family (also known as
E1-E2 ATPase), which is involved in transporting certain
ions, metals, and
lipids across the plasma membrane of mammalian cells. In humans, the Na(+) /K(+) -
ATPase is a binary complex of an α-subunit that has four
isoforms (α1 -α4 ) and a β-subunit that has three
isoforms (β1 -β3 ). This review aims to update our knowledge on the role of Na(+) /K(+) -
ATPase in
cancer development and
metastasis, as well as on how Na(+) /K(+) -
ATPase inhibitors kill tumour cells. The Na(+) /K(+) -
ATPase has been found to be associated with
cancer initiation, growth, development, and
metastasis.
Cardiac glycosides have exhibited anticancer effects in cell-based and mouse studies via inhibition of the Na(+) /K(+) -
ATPase and other mechanisms. Na(+) /K(+) -
ATPase inhibitors may kill
cancer cells via induction of apoptosis and autophagy,
radical oxygen species production, and cell cycle arrest. They also modulate multiple signalling pathways that regulate
cancer cell survival and death, which contributes to their antiproliferative activities in
cancer cells. The clinical evidence supporting the use of Na(+) /K(+) -
ATPase inhibitors as anticancer drugs is weak. Several phase I and phase II clinical trials with
digoxin,
Anvirzel, and
huachansu (an intravenous formulated extract of the
venom of the wild toad), either alone or more often in combination with other
anticancer agents, have shown acceptable safety profiles but limited efficacy in
cancer patients. Well-designed randomized clinical trials with reasonable sample sizes are certainly warranted to confirm the efficacy and safety of
cardiac glycosides for the treatment of
cancer.