Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action.
Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action.
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发表时间：
2002-05
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通讯作者：
Chunlei Zhang;P. Hazarika;X. Ni;D. Weidner;M. Duvic
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作者：
Chunlei Zhang;P. Hazarika;X. Ni;D. Weidner;M. Duvic
贝沙罗汀是第一个被批准用于治疗所有阶段皮肤t细胞淋巴瘤（CTCL）的合成维甲素类药物，但贝沙罗汀的作用机制尚不清楚。我们研究了贝沙罗汀在成熟的CTCL细胞系中诱导细胞凋亡及其同源受体表达的作用（MJ， Hut78和HH）。实验设计：用0.1、1和10微米贝沙罗汀分别处理CTCL细胞24、48、72和96小时。通过流式细胞术分析亚g(1)次二倍体细胞核和膜联蛋白V结合群体的凋亡情况。Western blot检测凋亡相关蛋白和类视黄醛受体。结果：与对照（DMSO）相比，贝沙罗汀在1和10微米下处理96小时，在所有三种细胞系中，亚g1群体和膜联蛋白V结合的细胞数量分别以剂量依赖的方式增加。与未处理的对照组相比，贝沙罗汀处理抑制了所有三种细胞系维甲酸受体α和维甲酸受体α蛋白的表达。贝沙罗汀处理降低了三种CTCL细胞系的survivin、活化caspase-3和cleaved poly（adp -核糖）聚合酶的蛋白水平，但对Fas/Fas配体和bcl-2蛋白的表达无明显影响。结论贝沙罗汀治疗CTCL细胞凋亡与caspase-3的激活、聚腺苷核糖聚合酶的裂解以及维甲酸受体α、维甲酸受体α和survivin的下调有关。这些发现支持细胞凋亡是贝沙罗汀治疗CTCL的一种机制。
PURPOSE Bexarotene is the first synthetic rexinoid approved for the treatment of all stages of cutaneous T-cell lymphoma (CTCL) however the mechanism of bexarotene action is unknown. We examined the effects of bexarotene on induction of apoptosis and expression of its cognate receptors in well-established CTCL cell lines (MJ, Hut78, and HH). EXPERIMENTAL DESIGN CTCL cells were treated with 0.1, 1, and 10 microM bexarotene for 24, 48, 72, and 96 h. Apoptosis was determined by flow-cytometry analysis of sub-G(1) hypodiploid nuclei and annexin V binding populations. Apoptosis-associated proteins and retinoid receptors were detected by Western blots. RESULTS Bexarotene treatment at 1 and 10 microM for 96 h increased the number of cells with sub-G1 populations and annexin V binding in a dose-dependent manner compared with vehicle controls (DMSO) in all three cell lines, respectively. Bexarotene treatment suppressed the expression of retinoid X receptor alpha and retinoic acid receptor alpha proteins in all three lines compared with untreated controls. Bexarotene treatment decreased the protein levels of survivin, activated caspase-3, and cleaved poly(ADP-Ribose) polymerase, but had no obvious effect on expression of Fas/Fas ligand and bcl-2 proteins in all three CTCL lines. CONCLUSIONS Bexarotene treatment at clinically relevant concentrations causes apoptosis of CTCL cell lines in association with activation of caspase-3 and cleavage of poly(ADP-Ribose) polymerase, as well as down-regulation of retinoid X receptor alpha, retinoic acid receptor alpha, and survivin. These findings support apoptosis as a mechanism for bexarotene therapy in CTCL.