Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis.
Monensin, an Na(+) ionophore, regulates many cellular functions including apoptosis. However, there has been no report about the antitumoral effect of monensin on acute myelogenous leukemia (AML). Here, we investigated the antiproliferative effect of monensin on AML cells in vitro and in vivo. Monensin efficiently inhibited the proliferation of all of 10 AML cell lines, with IC(50) of about 0.5 microM. DNA flow cytometric analysis indicated that monensin induced a G(1) and/or a G(2)-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of monensin on cell cycle-related proteins in HL-60 cells. The levels of CDK6, cyclin D1 and cyclin A were decreased. In addition, monensin not only increased the p27 level but also enhanced its binding with CDK2. Furthermore, the activities of CDK2- and CDK6-associated kinases reduced by monensin were associated with hypophosphorylation of Rb protein. Monensin also induced apoptosis in AML cells including HL-60 cells. The apoptotic process of HL-60 cells was associated with changes in Bax, caspase-3, caspase-8 and mitochondria transmembrane potential (Deltapsi(m)). In particular, monensin (i.p. at a dose of 8 mg/kg thrice weekly) significantly reduced the tumor size of BALB/c mice that were inoculated s.c. with its derived cell line, WEHI-3BD cells (69% growth inhibition relative to control group; p < 0.05). Tumors from monensin-treated mice exhibited increased apoptosis, and these tumor were immunohistochemically more stained with Bax, Fas and p53 antibodies than control tumors. In conclusion, this is the first report that monensin potently inhibits the proliferation of AML cells.
Park
Woo H
WH
Cancer Research Institute, Seoul National University College of Medicine, Korea.
Lee
Myung S
MS
Park
Keunchil
K
Kim
Eun S
ES
Kim
Byoung K
BK
Lee
Young Y
YY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007476:Ionophores / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008985:Monensin / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D007476:Ionophores; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008985:Monensin; D011065:Poly(ADP-ribose) Polymerases; D018844:Cyclin-Dependent Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases