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Monensin‐mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis
Author(s) -
Park Woo H.,
Lee Myung S.,
Park Keunchil,
Kim Eun S.,
Kim Byoung K.,
Lee Young Y.
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10592
Subject(s) - monensin , apoptosis , cell growth , cell cycle , cell culture , microbiology and biotechnology , growth inhibition , biology , cyclin d1 , chemistry , cancer research , biochemistry , genetics
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 μM. 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 (Δψ 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. © 2002 Wiley‐Liss, Inc.