Konopleva Marina, Tsao Twee, Estrov Zeev, Lee Ruey-min, Wang Rui-Yu, Jackson C Ellen, McQueen Teresa, Monaco Giuseppe, Munsell Mark, Belmont John, Kantarjian Hagop, Sporn Michael B, Andreeff Michael
Section of Molecular Hematology and Therapy and the Department of Blood and Marrow Transplantation at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Cancer Res. 2004 Nov 1;64(21):7927-35. doi: 10.1158/0008-5472.CAN-03-2402.
In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspase-independent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrial-mediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.
在急性髓系白血病（AML）中，对化疗的耐药性与凋亡的外源性和内源性途径缺陷相关。直接激活内源性凋亡诱导机制的新型药物可能对克服AML中的化疗耐药性具有潜在作用。我们研究了新型合成三萜类化合物2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸（CDDO）在AML细胞中诱导凋亡的机制。CDDO诱导的凋亡与AML细胞线粒体跨膜电位丧失、半胱天冬酶激活、凋亡诱导因子转位至细胞核以及DNA片段化有关。暴露于CDDO后，在缺乏半胱天冬酶-9或半胱天冬酶-8的细胞中凋亡同样明显，提示存在不依赖半胱天冬酶的细胞死亡。使用小干扰RNA降低凋亡诱导因子的表达可部分抑制AML细胞中CDDO诱导的凋亡。过表达Bcl-2的细胞对CDDO诱导的凋亡具有明显抗性。此外，CDDO促进了分离线粒体中细胞色素c的释放，表明CDDO直接靶向线粒体以触发完整细胞中细胞死亡的内源性途径。总之，这些结果表明CDDO通过激活凋亡的内源性途径发挥作用，并启动依赖半胱天冬酶和不依赖半胱天冬酶的细胞死亡。CDDO对线粒体介导的、不依赖半胱天冬酶的凋亡的直接调节可能有利于克服AML中的化疗耐药性。
