A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors.
A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors.
复制标题
DOI：
10.4161/cbt.25941
复制
发表时间：
2013-10-01
影响因子：
3.6
通讯作者：
Smith CL
中科院分区：
文献类型：
--
作者：
Tula-Sanchez AA;Havas AP;Alonge PJ;Klein ME;Doctor SR;Pinkston W;Glinsmann-Gibson BJ;Rimsza LM;Smith CL
弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性非霍奇金淋巴瘤。虽然最初的治疗策略非常有效，但40%的病例会复发。组蛋白去乙酰化酶抑制剂（HDACi）是一类有前途的抗癌药物，但其针对复发性DLBCL的单一药剂功效是可变的，范围从很少的完全/部分响应到一些稳定的疾病。然而，大多数患者对HDACi单药治疗没有反应，原因不明。在这里，我们显示了对异羟肟酸HDACi，PXD 101的敏感性和抗性可以在DLBCL细胞系中建模。敏感性的特征是G2/M停滞和细胞凋亡，而耐药性的特征是可逆的G1生长停滞。这些对PXD 101的反应不依赖于几种阴性预后指标，如DLBCL亚型、BCL 2和MYC共表达和p53突变，这表明如果HDACi与克服HDACi耐药性的其他治疗剂组合，HDACi可能有效地用于对抗高度侵袭性DLBCL肿瘤。我们对HDACi耐药机制的研究表明，PXD 101以持续的方式上调细胞周期蛋白依赖性激酶抑制剂（CKIs）p21和p27，伴随着细胞周期蛋白E/cdk 2复合物活性的降低和Rb磷酸化的降低。PXD 101处理导致CKI与细胞周期蛋白E/cdk 2复合物在抗性细胞系中的关联增加，但在敏感细胞系中没有，表明CKI在G1期阻滞中起关键作用。结果表明，几种治疗策略可能会增加HDACi对侵袭性DLBCL的疗效。
Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G2/M arrest and apoptosis and resistance by reversible G1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL.
登录
查看更多内容
影响因子：
20.3
作者：
Gupta, Mamta;Ansell, Stephen M.;Witzig, Thomas E.
通讯作者：
Witzig, Thomas E.
组蛋白脱乙酰基酶抑制剂trichostatin A在MCF-7乳腺癌细胞中诱导泛素依赖性细胞周期蛋白D1降解。
影响因子：
37.3
作者：
Alao, John P;Stavropoulou, Alexandra V;Lam, Eric W-F;Coombes, R Charles;Vigushin, David M
通讯作者：
Vigushin, David M
影响因子：
6.5
作者：
Gloghini A;Buglio D;Khaskhely NM;Georgakis G;Orlowski RZ;Neelapu SS;Carbone A;Younes A
通讯作者：
Younes A
影响因子：
8
作者：
Huang, LL;Sowa, Y;Pardee, AB
通讯作者：
Pardee, AB
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM