2-Methoxyestradiol blocks cell-cycle progression at the G2/M phase and induces apoptosis in human acute T lymphoblastic leukemia CEM cells.
2-Methoxyestradiol (2-ME2) is an endogenous metabolite of 17beta-estradiol (E2) with estrogen receptor-independent anti-cancer activity. The current study sought to determine the mechanism of anti-cancer activity of 2-ME2 in human acute T lymphoblastic leukemia CEM cells. Results showed that 2-ME2 markedly suppressed proliferation of CEM cells in a time- and dose-dependent manner. 2-ME2-treated CEM cells underwent typical apoptotic changes. Exposure to 2-ME2 led to G(2)/M phase cell-cycle arrest, which preceded apoptosis characterized by the appearance of a sub-G(1) cell population. In addition, cytosolic cytochrome c release, increased procaspase-9 and -3 expressions, poly(ADP-ribose) polymerase (PARP) cleavage, and induced expression of caspase-8 were detected, suggesting that both the intrinsic apoptotic pathway and extrinsic apoptotic pathway were involved in 2-ME2-induced apoptosis. Moreover, the expression level of p21 protein was upregulated, whereas Bcl-2 and dysfunctional p53 protein were downregulated, which also contributed to 2-ME2-induced apoptosis. Our findings revealed that 2-ME2 might be a potent natural candidate for chemotherapeutic treatment of human acute T lymphoblastic leukemia when the precise effects of 2-ME2 were investigated further in other T leukemia cell lines and in primary T-cell leukemias.
Zhang
Xueya
X
Department of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
Huang
Haobo
H
Xu
Zhenshu
Z
Zhan
Rong
R
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019253:Proto-Oncogene Proteins c-bcl-2; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000077584:2-Methoxyestradiol