Increased manganese superoxide dismutase expression or treatment with manganese porphyrin potentiates dexamethasone-induced apoptosis in lymphoma cells.
Increased manganese superoxide dismutase expression or treatment with manganese porphyrin potentiates dexamethasone-induced apoptosis in lymphoma cells.
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DOI：
10.1158/0008-5472.can-08-4031
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Tome ME
中科院分区：
文献类型：
--
作者：
Jaramillo MC;Frye JB;Crapo JD;Briehl MM;Tome ME
糖皮质激素诱导的细胞凋亡被用于治疗恶性血液病。先天性和获得性耐药性限制了治疗效果;然而，耐药性机制尚未得到很好的理解。以前，使用WEHI7.2小鼠胸腺淋巴瘤细胞，我们发现，增加过氧化氢的抗性过氧化氢酶转染或选择过氧化氢抗性导致糖皮质激素抗性。这表明增加过氧化氢敏感性可能会使细胞对糖皮质激素敏感。在其他细胞类型中，增加锰超氧化物歧化酶（MnSOD）可以增加细胞内过氧化氢。目前的研究表明，MnSOD的表达增加敏感WEHI7.2细胞糖皮质激素诱导的凋亡和过氧化氢。用催化抗氧化剂Mn（III）meso-四（N-乙基吡啶-2-基）卟啉（MnTE-2-PyP 5+）（一种锰卟啉）处理WEHI 7.2细胞，模拟了MnSOD表达增加的作用。MnTE-2-PyP 5+也使WEHI7.2细胞对环磷酰胺敏感并抑制细胞生长;它对WEHI7.2细胞对多柔比星或长春新碱的反应没有影响。在原发性滤泡性淋巴瘤细胞中，MnTE-2-PyP 5+增加了地塞米松引起的细胞死亡。用MnTE-2-PyP 5+处理H9 c2心肌细胞抑制阿霉素的细胞毒性。MnTE-2-PyP 5+作用的特征表明MnTE-2-PyP 5+具有用于用糖皮质激素、环磷酰胺和多柔比星治疗的血液恶性肿瘤的潜力。
Glucocorticoid-induced apoptosis is exploited for the treatment of hematologic malignancies. Innate and acquired resistance limits treatment efficacy; however, resistance mechanisms are not well understood. Previously, using WEHI7.2 murine thymic lymphoma cells, we found that increasing the resistance to hydrogen peroxide by catalase transfection or selection for hydrogen peroxide resistance caused glucocorticoid resistance. This suggests the possibility that increasing hydrogen peroxide sensitivity could sensitize the cells to glucocorticoids. In other cell types, increasing manganese superoxide dismutase (MnSOD) can increase intracellular hydrogen peroxide. The current study demonstrated that increased expression of MnSOD sensitized WEHI7.2 cells to glucocorticoid-induced apoptosis and hydrogen peroxide. Treatment of WEHI7.2 cells with the catalytic antioxidant Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP5+), a manganoporphyrin, mimicked the effects of increased MnSOD expression. MnTE-2-PyP5+ also sensitized WEHI7.2 cells to cyclophosphamide and inhibited cell growth; it had no effect on the WEHI7.2 cell response to doxorubicin or vincristine. In primary follicular lymphoma cells, MnTE-2-PyP5+ increased cell death due to dexamethasone. Treatment of H9c2 cardiomyocytes with MnTE-2-PyP5+ inhibited doxorubicin cytotoxicity. The profile of MnTE-2-PyP5+ effects suggests MnTE-2-PyP5+ has potential for use in hematologic malignancies that are treated with glucocorticoids, cyclophosphamide and doxorubicin.