吉西他滨
核苷酸还原酶
脱氧胞苷
癌症研究
套细胞淋巴瘤
细胞培养
联合疗法
生物
化学
药理学
淋巴瘤
医学
蛋白质亚单位
内科学
化疗
免疫学
生物化学
基因
遗传学
作者
Richard J. Jones,Veerabhadran Baladandayuthapani,Sattva S. Neelapu,Luis Fayad,Jorge Romaguera,Michael Wang,Rakesh Sharma,Dajun Yang,Robert Z. Orłowski
出处
期刊:Blood
[American Society of Hematology]
日期:2011-10-13
卷期号:118 (15): 4140-4149
被引量:37
标识
DOI:10.1182/blood-2011-03-340323
摘要
Mantle cell lymphoma (MCL) usually responds well to initial therapy but is prone to relapses with chemoresistant disease, indicating the need for novel therapeutic approaches. Inhibition of the p53 E3 ligase human homolog of the murine double minute protein-2 (HDM-2) with MI-63 has been validated as one such strategy in wild-type (wt) p53 models, and our genomic and proteomic analyses demonstrated that MI-63 suppressed the expression of the ribonucleotide reductase (RNR) subunit M2 (RRM2). This effect occurred in association with induction of p21 and cell-cycle arrest at G(1)/S and prompted us to examine combinations with the RNR inhibitor 2',2'-difluoro-2'-deoxycytidine (gemcitabine). The regimen of MI-63-gemcitabine induced enhanced, synergistic antiproliferative, and proapoptotic effects in wtp53 MCL cell lines. Addition of exogenous dNTPs reversed this effect, whereas shRNA-mediated inhibition of RRM2 was sufficient to induce synergy with gemcitabine. Combination therapy of MCL murine xenografts with gemcitabine and MI-219, the in vivo analog of MI-63, resulted in enhanced antitumor activity. Finally, synergy was seen with MI-63-gemcitabine in primary patient samples that were found to express high levels of RRM2 compared with MCL cell lines. These findings provide a framework for translation of the rational combination of an HDM-2 and RNR inhibitor to the clinic for patients with relapsed wtp53 MCL.
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