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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1427-1434
Apoptosis of leukemic cells accompanies reduction in intracellular
pH after targeted inhibition of the Na+/H+
exchanger
Ivan N. Rich,
Diana Worthington-White,
Oliver A. Garden, and
Philip Musk
From the Division of Transplantation Medicine, South Carolina Cancer
Center, Palmetto Richland Memorial Hospital, Columbia, SC.
The Na+/H+ exchanger isoform 1 (NHE1) is
primarily responsible for the regulation of intracellular pH
(pHi). It is a ubiquitous, amiloride-sensitive, growth
factor-activatable exchanger whose role has been implicated in
cell-cycle regulation, apoptosis, and neoplasia. Here we demonstrate
that leukemic cell lines and peripheral blood from primary patient
leukemic samples exhibit a constitutively and statistically higher
pHi than normal hematopoietic tissue. We then show that a
direct correlation exists between pHi and cell-cycle status
of normal hematopoietic and leukemic cells. Advantage was taken of this
relationship by treating leukemic cells with the
Na+/H+ exchanger inhibitor, 5-(N,
N-hexamethylene)-amiloride (HMA), which decreases the pHi
and induces apoptosis. By incubating patient leukemic cells in vitro
with pharmacologic doses of HMA for up to 5 hours, we show, using flow
cytometry and fluorescent ratio imaging microscopy, that when the
pHi decreases, apoptosis measured by annexin-V and TUNEL
methodologiesrapidly increases so that more than 90% of the
leukemic cells are killed. The differential sensitivity exhibited
between normal and leukemic cells allows consideration of NHE1
inhibitors as potential antileukemic agents.
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