Betuletol 3-methyl ether induces G 2 -M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells
2009; Wiley; Volume: 49; Issue: 1 Linguagem: Inglês
10.1002/mc.20574
ISSN1098-2744
AutoresSara Rubio, José Quintana, José Luis Eiroa, Jorge Triana, Francisco Estévez,
Tópico(s)Natural product bioactivities and synthesis
ResumoMolecular CarcinogenesisVolume 49, Issue 1 p. 32-43 Research Article Betuletol 3-methyl ether induces G2-M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells Sara Rubio, Sara Rubio Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorJosé Quintana, José Quintana Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorJosé L. Eiroa, José L. Eiroa Department of Chemistry, Instituto Canario de Investigación del Cáncer, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorJorge Triana, Jorge Triana Department of Chemistry, Instituto Canario de Investigación del Cáncer, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorFrancisco Estévez, Corresponding Author Francisco Estévez Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainDepartment of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Plaza Dr Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.Search for more papers by this author Sara Rubio, Sara Rubio Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorJosé Quintana, José Quintana Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorJosé L. Eiroa, José L. Eiroa Department of Chemistry, Instituto Canario de Investigación del Cáncer, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorJorge Triana, Jorge Triana Department of Chemistry, Instituto Canario de Investigación del Cáncer, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainSearch for more papers by this authorFrancisco Estévez, Corresponding Author Francisco Estévez Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, SpainDepartment of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Plaza Dr Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.Search for more papers by this author First published: 12 August 2009 https://doi.org/10.1002/mc.20574Citations: 16Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Betuletol 3-methyl ether (BME) is a natural phenylbenzo-γ-pyrone that inhibits cell proliferation in human tumor cell lines and induces apoptotic cell death in HL-60 cells. Here we show that BME displays strong cytotoxic properties in several human leukemia cell lines (U937, K-562, THP-1, Jurkat, and Molt-3) and in cells that over-express two anti-apoptotic proteins, namely Bcl-2 and Bcl-xL. BME arrested HL-60 cells at G2-M phase of the cell cycle, which was associated with the accumulation of cyclin B1 and p21Cip1. Fluorescence microscopy experiments suggest that BME blocked the cell cycle in mitosis. The in vivo tubulin polymerization assay shows that BME inhibits tubulin polymerization and causes similar changes of cellular microtubule network as colchicine. Our results demonstrate that BME-induced cell death is (i) triggered in human myeloid leukemia cell that over-express Bcl-2 and Bcl-xL, and (ii) associated with loss of inner mitochondrial membrane potential (ΔΨm) and an increase in reactive oxygen species (ROS). Although ROS increased in response to BME, this did not seem to play a pivotal role in the apoptotic process since the anti-oxidant trolox was unable to provide cell protection. The treatment of HL-60 cells with BME induces the activation of mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases, p38 mitogen-activated protein kinases and extracellular signal-regulated kinases (ERK)1/2 and stimulates the acid sphingomyelinase with concomitant ceramide generation. The findings of this study suggest that BME could be useful in the development of novel anticancer agents. © 2009 Wiley-Liss, Inc. Citing Literature Volume49, Issue1January 2010Pages 32-43 RelatedInformation
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