Resveratrol increases rate of apoptosis caused by purine analogues in malignant lymphocytes of chronic lymphocytic leukemia.
Resveratrol increases rate of apoptosis caused by purine analogues in malignant lymphocytes of chronic lymphocytic leukemia.
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白藜芦醇增加了由慢性淋巴细胞性白血病恶性淋巴细胞中嘌呤类似物引起的凋亡率。
DOI：
10.1007/s00277-010-1045-7
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发表时间：
2011-02
影响因子：
3.5
通讯作者：
Dmoszynska, Anna
中科院分区：
文献类型：
--
作者：
Podhorecka, Monika;Halicka, Dorota;Klimek, Piotr;Kowal, Malgorzata;Chocholska, Sylwia;Dmoszynska, Anna
在这项研究中，我们试图评估白藜芦醇(一种存在于各种植物中的天然化合物)与嘌呤类似物氟达拉滨和克拉立滨对慢性淋巴细胞白血病(CLL)细胞DNA损伤和凋亡的影响。这些实验是使用新诊断的未经治疗的患者的血液和骨髓细胞的短期细胞培养在体外进行的。分析细胞凋亡标志物半胱氨酸天冬氨酸氨基转移酶-3的活性和bcl2/bax的比值，以及反映γ损伤的磷酸化的组蛋白H_2AX和激活的ATMK的表达。我们的研究结果表明，白藜芦醇以肿瘤特异性的方式诱导CLL细胞凋亡，但不影响非白血病细胞，并且凋亡与bcl2/bax比率降低有关。在这里，我们首次报道了白藜芦醇+氟达拉滨和白藜芦醇+克拉立滨与单一药物引起的细胞凋亡率相比，两者都有更高的凋亡率。在预后标志较好的患者组中，白藜芦醇单独诱导的凋亡细胞百分比高于预后标志较差的患者。然而，白藜芦醇联合嘌呤类似物引起的凋亡率与ZAP-70和CD38的表达以及疾病的临床状态无关；它们仅取决于是否存在高危细胞遗传学异常。我们还观察到，在大多数分析样本中，γH2 AX的表达增加，同时激活的ATM量也增加。这些结果表明，白藜芦醇可能值得进一步研究作为CLL患者的一种新的治疗选择。这种自然产生的物质可以用作单一制剂，特别是在老年人中，对他们来说，使用积极的治疗是有一定限制的。另一方面，较低的嘌呤类似物剂量可能与白藜芦醇联合使用，因为它们的联合作用。白藜芦醇的作用机制之一是诱导DNA损伤，最终导致细胞凋亡。
In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (γH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in γH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis.
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影响因子：
3.5
作者：
Ami, AS;Bhat, SH;Hadi, SM
通讯作者：
Hadi, SM
影响因子：
3.5
作者：
Fontecave, M;Lepoivre, M;Guittet, O
通讯作者：
Guittet, O
影响因子：
11.4
作者：
Giannopoulos, K.;Dmoszynska, A.;Bullinger, L.
通讯作者：
Bullinger, L.
影响因子：
158.5
作者：
Crespo, M;Bosch, F;Montserrat, E
通讯作者：
Montserrat, E
影响因子：
20.3
作者：
Kurtova, Antonina V.;Balakrishnan, Kumudha;Burger, Jan A.
通讯作者：
Burger, Jan A.