The triterpenoid CDDO induces apoptosis in refractory CLL B cells
The triterpenoid CDDO induces apoptosis in refractory CLL B cells
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DOI：
10.1182/blood-2002-04-1174
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发表时间：
2002-10-15
期刊：
影响因子：
20.3
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Pedersen, IM;Kitada, S;Reed, JC
慢性淋巴细胞白血病（CLL）细胞随着时间的推移而产生化学抗性。大多数抗癌药物通过诱导细胞凋亡发挥作用，因此对这些药物的耐药性可能是由选择在这些药物触发的特定细胞凋亡途径中具有缺陷的CLL细胞引起的。因此，通过替代凋亡途径发挥作用的抗癌剂可能有助于治疗化疗耐药的CLL。三萜类化合物代表一类天然存在的和合成的化合物，具有已证实的抗肿瘤活性。我们研究了三萜类化合物2-氰基-3，12-二氧代-1，9-二烯-28-酸（CDDO）对体外CLL B细胞的作用。CDDO以剂量依赖性方式在所有（n = 30）测试的CLL样品中诱导细胞凋亡，包括先前未处理的和化学抗性的CLL标本。在CLL B细胞中，CDDO诱导半胱天冬酶-8但不诱导半胱天冬酶-9的快速蛋白水解加工，这表明激活了非依赖于caspase的途径。CDDO诱导的CLL B细胞凋亡可被caspase-8的抑制因子细胞因子反应调节剂A（CrmA）阻断，但不能被选择性抑制caspase-9的XIAP片段凋亡抑制蛋白-杆状病毒IAP重复序列3（XIAP-BIR3）阻断。检查CDDO对几种糖尿病相关基因表达的影响表明，caspase-8同系物Fas配体白细胞介素-11转换酶（FLICE）抑制蛋白（c-FLIP）（caspase-8的内源性拮抗剂）的水平显著降低。然而，通过FLIP反义寡核苷酸实现的FLIP的减少不足以触发细胞凋亡，表明CDDO在CLL B细胞中具有除FLIP之外的其他靶标。这些数据表明，合成的三萜类化合物CDDO应进一步探索作为一种可能的治疗药物，用于治疗化疗耐药CLL。
Chronic lymphocytic leukemia (CLL) cells develop chemo-resistance over time. Most anticancer agents function through induction of apoptosis, and therefore resistance against these agents is likely to be caused by selection for CLL cells with defects in the particular apoptosis pathway that is triggered by these drugs. Anticancer agents that function through alternative apoptotic pathways might therefore be useful in treating chemoresistant CLL. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity. We examined the effects of CDDO (triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) on CLL B cells in vitro. CDDO induced apoptosis in a dose-dependent manner in all (n=30) CLL samples tested, including previously untreated and chemo-resistant CLL specimens. CDDO induced rapid proteolytic processing of caspase-8, but not caspase-9, in CLL B cells, suggesting activation of a mitochondria-independent pathway. CDDO-incluced apoptosis of CLL B cells was blocked by cytokine response modifier A (CrmA), a suppressor of caspase-8, but not by X-linked inhibitor of apoptosis protein-baculovirus IAP repeat-3 (XIAP-BIR3), a fragment of XIAP, which selectively inhibits caspase-9. Examination of CDDO effects on expression of several apoptosis-relevant genes demonstrated significant reductions in the levels of caspase-8 homolog Fas-ligand interleukin-11-converting enzyme (FLICE)inhibitory protein (c-FLIP), an endogenous antagonist of caspase-8. However, reductions of FLIP achieved by FLIP antisense oligonucleotides were insufficient for triggering apoptosis, indicating that CDDO has other targets in CLL B cells besides FLIP. These data suggest that the synthetic triterpenoid CDDO should be further explored as a possible therapeutic agent for treatment of chemo-resistant CLL.