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Title: Betuletol 3-methyl ether induces G2-M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells
Authors: Rubio Sánchez, Sara 
Quintana Aguiar, José Martín 
Eiroa, José L. 
Triana, Jorge
Estévez Rosas, Francisco Jesús 
UNESCO Clasification: 241010 Fisiología humana
320101 Oncología
Keywords: Apoptosis
Cell cycle arrest
Mitogen-activated protein kinases
C-JunN-terminal kinases, et al
Issue Date: 2010
Publisher: 0899-1987
Project: Desarrollo de Nuevos, Mas Seguros y Mas Efectivos Compuestos Antileucemicos 
Journal: Molecular Carcinogenesis 
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.
ISSN: 0899-1987
DOI: 10.1002/mc.20574
Source: Molecular Carcinogenesis [ISSN 0899-1987],v. 49 (1), p. 32-43
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