Early changes in metabolism of leukemic cell lines upon induction of apoptosis by cytotoxic drugs.
We evaluated real-time changes in extracellular acidification rates of human U937 and K562 leukemic cells treated with camptothecin or taxol. U937 cells treated with camptothecin or taxol for 30-60 min showed a continuous, irreversible decrease in extracellular acidification rate that was sensitive to amiloride. In contrast, U937 cells exposed to sodium azide showed an immediate, steep decrease in extracellular acidification rate that was reversible upon azide withdrawal. K562 cells required a >20-fold higher dose of camptothecin to promote similar changes in the extracellular acidification rate, with a corresponding resistance in their susceptibility to camptothecin- or taxol-induced apoptosis. The data show that irreversible commitment to apoptosis is associated with rapid metabolic changes that are reflected by decreased extracellular acidification rate and regulated by the Na(+)/H(+) antiporter. Moreover, detection of extracellular acidification rate changes was not restricted to a particular cell type or apoptosis pathway, making this a potentially useful tool to screen compounds for pro-apoptotic activity.
Khare
Sangeeta
S
Department of Pathobiology, Texas A&M University, College Station, TX, USA.
Banai
Yona
Y
Gokulan
Kuppan
K
Smith
Roger
R
Linthicum
Darwin S
DS
Modiano
Jaime F
JF
D000584:Amiloride / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D019810:Sodium Azide / Q000494:pharmacology; D020298:U937 Cells
D000972:Antineoplastic Agents, Phytogenic; D000584:Amiloride; D019810:Sodium Azide; D017239:Paclitaxel; D002166:Camptothecin