Monensin-mediated growth inhibition in human lymphoma cells through cell cycle arrest and apoptosis.
Monensin, a Na+ ionophore, regulates many cellular functions, including apoptosis. We investigated the in vitro antiproliferative effect of monensin on nine human lymphoma cell lines. Monensin significantly inhibited the proliferation of all the lymphoma cell lines examined with a 50% inhibition concentration of about 0.5 micromol/l, and induced a G1 and/or a G2-M phase arrest in these cell lines. To address the antiproliferative mechanism of monensin, we examined the effect of this drug on cell-cycle-related proteins in CA46 cells (both G1 and G2 arrest) and Molt-4 cells (G2 arrest). Treatment with monensin for 72 h decreased CDK4 and cyclin A levels in CA46 cells, and cdc2 levels in Molt-4 cells. In monensin-treated CA46 cells, increased p21-CDK2, p27-CDK2 and p27-CDK4 complex forms were observed. And, in monensin-treated Molt-4 cells, increased p21-cdc2 complex form was detected. Furthermore, the activities of CDK2- and CDK4-associated kinases were reduced in association with Rb hypophosphorylation in monensin-treated CA46 cells. The activity of cdc2-associated kinase was decreased in both cell lines, which was accompanied by induction of Wee1. Also, monensin induced apoptosis in these cell lines, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with loss of mitochondria transmembrane potential (Delta(psi)m). Taken together, these results demonstrated for the first time that monensin potently inhibits the proliferation of human lymphoma cell lines via cell cycle arrest and apoptosis.
Park
Woo Hyun
WH
Cancer Research Institute, Seoul National University College of Medicine, Korea.
Seol
Jae Goo
JG
Kim
Eun Shil
ES
Kang
Won Ki
WK
Im
Young Hyuck
YH
Jung
Chul Won
CW
Kim
Byoung Kook
BK
Lee
Young Yiul
YY
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D007399:Interphase; D007476:Ionophores / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy; D008564:Membrane Potentials / Q000187:drug effects; D008985:Monensin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
C493956:CDKN1A protein, human; D019925:Cyclin A; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007476:Ionophores; D008985:Monensin; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases