Anti-leukemic effects of the V-ATPase inhibitor Archazolid A.
Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL.
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany.
Siwei
S
Zhang
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany.
Lina S
LS
Schneider
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Binje
B
Vick
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
Michaela
M
Grunert
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|Department of Oncology/Hematology, Dr. von Haunersches Kinderspital, Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Irmela
I
Jeremias
Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Bonn, Germany.
Dirk
D
Menche
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
Rolf
R
Müller
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany.
Angelika M
AM
Vollmar
Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany.
Johanna
J
Liebl
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014162:Transfection; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018942:Macrolides; D013844:Thiazoles; C519727:archazolid A; D025262:Vacuolar Proton-Translocating ATPases
Archazolid; leukemia; natural compounds