Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase p1-1.
OBJECTIVE
Arsenic trioxide (ATO) as a single agent is used for treatment of acute promyelocytic leukemia (APL) with minimal toxicity, but therapeutic effect of ATO in other types of malignancies has not been achieved. We tested whether a combination with ethacrynic acid (EA), a glutathione S-transferase P1-1 (GSTP1-1) inhibitor, and a reactive oxygen species (ROS) inducer will extend the therapeutic effect of ATO beyond APL.


METHODS
The combined apoptotic effects of ATO plus ethacrynic acid were tested in non-APL leukemia and lymphoma cell lines. The role of ROS, GSTP1-1, glutathione (GSH), and Mcl-1 in apoptosis was determined. The selective response to this combination of cells with and without GSTP1-1 expression was compared.


RESULTS
ATO/EA combination synergistically induced apoptosis in myeloid leukemia and lymphoma cells. This treatment produced high ROS levels, activated c-jun-NH(2)-kinase (JNK), and reduced Mcl-1 protein. This led to the decrease of mitochondrial transmembrane potential, release of cytochrome c, and subsequently, to activation of caspase-3 and -9. Induction of apoptosis in leukemia and lymphoma cells expressing GSTP1-1 required high ethacrynic acid concentrations to be combined with ATO. Silencing of GSTP1 in leukemia cells sensitized them to ATO/EA-induced apoptosis. In a subgroup of B-cell lymphoma, which does not express GSTP1-1, lower concentrations of ethacrynic acid and its more potent derivative, ethacrynic acid butyl-ester (EABE), decreased intracellular GSH levels and synergistically induced apoptosis when combined with ATO.


CONCLUSIONS
B-cell lymphoma cells lacking GSTP1-1 are more sensitive than myeloid leukemia cells to ATO/EA-induced apoptosis.
The Division of Hematology/Oncology, Department of Medicine, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York 10029, USA.
Rui
R
Wang
Changda
C
Liu
Lijuan
L
Xia
Guisen
G
Zhao
Janice
J
Gabrilove
Samuel
S
Waxman
Yongkui
Y
Jing
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation; D004976:Ethacrynic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid; D008223:Lymphoma; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001152:Arsenicals; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C581245:ethacrynic acid butyl ester; D002374:Catalase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D048670:MAP Kinase Kinase 4; D020169:Caspases; D005978:Glutathione; D004976:Ethacrynic Acid; D000077237:Arsenic Trioxide