Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia
Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia
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DOI：
10.1111/j.1365-2141.2010.08425.x
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发表时间：
2011-01-01
影响因子：
6.5
通讯作者：
Willmore, Elaine
中科院分区：
文献类型：
--
作者：
Elliott, Sarah L.;Crawford, Clark;Willmore, Elaine
DNA损伤反应通路中的缺陷[如del(17p)]与耐药b细胞慢性淋巴细胞白血病（CLL）有关。我们之前证明了dna依赖性蛋白激酶（DNA-PK）的过度表达与化疗耐药相关，并且DNA-PK的抑制使CLL细胞对化疗药物敏感。在这里，我们研究了DNA-PK和其他影响耐药的蛋白的表达，并评估了DNA-PK抑制剂（NU7441）对米托蒽醌诱导的CLL细胞毒性的影响。NU7441使42/49 CLL样本的细胞对米托蒽醌致敏，致敏性从2倍到200倍不等，在条件基质培养基中共同培养CLL细胞增加了化疗耐药，但没有降低NU7441的致敏性。米托蒽醌处理诱导的γ - H2AX灶和NU7441延长了它们的寿命（24 h）。NU7441阻止了米托蒽醌诱导的DNA- pk催化亚基（DNA- pkcs） Ser 2056位点的自磷酸化，证实了DNA- pk参与了米托蒽醌诱导的DNA损伤的修复。del（17p）对米托蒽醌的耐药程度高于del(13q)，但与NU7441共孵育后重新致敏（7-16倍）。del（17p）患者DNA-PKcs、Ku80、p -糖蛋白和拓扑异构酶II β的表达显著升高。PRKDC mRNA水平与DNA-PKcs蛋白表达相关，预测较短的生存期。这些数据证实了DNA-PK作为不良预后CLL治疗靶点的潜力。
P>Defects in the DNA damage response pathway [e.g. del(17p)] are associated with drug-resistant B-cell chronic lymphocytic leukaemia (CLL). We previously demonstrated that over-expression of DNA-dependent protein kinase (DNA-PK) correlates with chemo-resistance and that inhibition of DNA-PK sensitizes CLL cells to chemotherapeutics. Here, we investigated expression of DNA-PK and other proteins that impact on drug resistance, and evaluated the effects of a DNA-PK inhibitor (NU7441) on mitoxantrone-induced cytotoxicity in CLL cells. NU7441 sensitized cells from 42/49 CLL samples to mitoxantrone, with sensitization ranging from 2- to 200-fold Co-culture of CLL cells in conditioned stromal medium increased chemoresistance but did not reduce sensitization by NU7441. Mitoxantrone treatment induced gamma H2AX foci and NU7441 increased their longevity (24 h). NU7441 prevented mitoxantrone-induced autophosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) at Ser 2056, confirming that DNA-PK participates in repair of mitoxantrone-induced DNA damage. del(17p) cases were more resistant to mitoxantrone than del(13q) cases, but were resensitized (7-16 fold) by co-incubation with NU7441. Expression of DNA-PKcs, Ku80, P-glycoprotein and topoisomerase II beta were significantly higher in del(17p) cases. PRKDC mRNA levels correlated with DNA-PKcs protein expression, which predicted shorter survival. These data confirm the potential of DNA-PK as a therapeutic target in poor prognosis CLL.