VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia

被引:178
作者
Lee, YK
Bone, ND
Strege, AK
Shanafelt, TD
Jelinek, DF
Kay, NE
机构
[1] Mayo Clin & Mayo Fdn, Dept Med, Div Hematol, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Immunol, Rochester, MN 55905 USA
关键词
D O I
10.1182/blood-2003-08-2763
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We recently reported that chronic lymphocytic leukemia (CLL) cells synthesize and release vascular endothelial growth factor (VEGF) under normoxic and hypoxic conditions. CLL B cells also express VEGF membrane receptors (VEGF-R1 and VEGF-R2), suggesting that they use VEGF as a survival factor. To assess the mechanism of apoptosis resistance related to VEGF, we determined the impact of VEGF on CLL B cells, and we studied the impact of epigallocatechin-3-gallate (EGCG), a known receptor tyrosine kinase (RTK) inhibitor, on VEGF receptor status and viability of CLL B cells. VEGF(165) significantly increased apoptotic resistance of CLL B cells, and immunoblotting revealed that VEGF-R1 and VEGF-R2 are spontaneously phosphorylated on CLL B cells. EGCG significantly increased apoptosis/cell death in 8 of 10 CLL samples measured by annexin V/propidium iodide (PI) staining. The increase in annexin V/PI staining was accompanied by caspase-3 activation and poly-adenosine diphosphate ribose polymerase (PARP) cleavage at low concentrations of EGCG (3 mug/mL). Moreover, EGCG suppressed the proteins B-cell leukemia/lymphoma-2 protein (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and myeloid cell leukemia-1 (Mcl-1) in CLL B cells. Finally, EGCG (3-25 mug/mL) suppressed VEGF-R1 and VEGF-R2 phosphorylation, albeit incompletely. Thus, these results suggest that VEGF signaling regulates survival signals in CLL cells and that interruption of this autocrine pathway results in caspase activation and subsequent leukemic cell death.
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页码:788 / 794
页数:7
相关论文
共 48 条
[41]   Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis [J].
Niu, GL ;
Wright, KL ;
Huang, M ;
Song, LX ;
Haura, E ;
Turkson, J ;
Zhang, SM ;
Wang, TH ;
Sinibaldi, D ;
Coppola, D ;
Heller, R ;
Ellis, LM ;
Karras, J ;
Bromberg, J ;
Pardoll, D ;
Jove, R ;
Yu, H .
ONCOGENE, 2002, 21 (13) :2000-2008
[42]   Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia [J].
Padró, T ;
Ruiz, S ;
Bieker, R ;
Bürger, H ;
Steins, M ;
Kienast, J ;
Büchner, T ;
Berdel, WGE ;
Mesters, RM .
BLOOD, 2000, 95 (08) :2637-2644
[43]   Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1 [J].
Pedersen, IM ;
Kitada, S ;
Leoni, LM ;
Zapata, JM ;
Karras, JG ;
Tsukada, N ;
Kipps, TJ ;
Choi, YS ;
Bennett, F ;
Reed, JC .
BLOOD, 2002, 100 (05) :1795-1801
[44]   Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase C8 [J].
Ringshausen, I ;
Schneller, F ;
Bogner, C ;
Hipp, S ;
Duyster, J ;
Peschel, C ;
Decker, T .
BLOOD, 2002, 100 (10) :3741-3748
[45]   'Angioprevention': angiogenesis is a common and key target for cancer chemopreventive agents [J].
Tosetti, F ;
Ferrari, N ;
De Flora, S ;
Albini, A .
FASEB JOURNAL, 2002, 16 (01) :2-14
[46]   A single ascending dose study of epigallocatechin gallate in healthy volunteers [J].
Ullmann, U ;
Haller, J ;
Decourt, JP ;
Girault, N ;
Girault, J ;
Richard-Caubron, AS ;
Pineau, B ;
Weber, P .
JOURNAL OF INTERNATIONAL MEDICAL RESEARCH, 2003, 31 (02) :88-101
[47]  
Veikkola T, 2000, CANCER RES, V60, P203
[48]   The therapeutic potential of flavonoids [J].
Wang, HK .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2000, 9 (09) :2103-2119