Adamantyl-substituted retinoid-related molecules induce apoptosis in human acute myelogenous leukemia cells.
Adamantyl-substituted retinoid-related molecules induce apoptosis in human acute myelogenous leukemia cells.
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DOI：
10.1158/1535-7163.mct-10-0546
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发表时间：
2010-11
影响因子：
5.7
通讯作者：
Fontana JA
中科院分区：
文献类型：
--
作者：
Farhana L;Dawson MI;Xia Z;Aboukameel A;Xu L;Liu G;Das JK;Hatfield J;Levi E;Mohammad R;Fontana JA
金刚烷基取代的类视黄醇相关化合物 3-Cl-AHPC 和 AHP3 在体外和体内诱导新建立的人类 AML 细胞系 FFMA-AML 和已建立的 TF(v-SRC) AML 细胞系的细胞凋亡。 FFMA-AML 和 TF(v-SRC) 细胞在体外和体内表现出对标准类视黄酸（包括反式视黄酸、9 顺式视黄酸和合成类视黄酸 TTNPB）介导的细胞凋亡的抗性，但对 3-Cl-AHPC 和 AHP3 介导的细胞凋亡敏感，如 PARP 裂解和细胞凋亡 TUNEL 测定所记录。体外暴露 3-Cl-AHPC 或 AHP3 会导致抗凋亡蛋白（c-IAP1、XIAP）和磷酸-Bad 表达降低，并激活 NF-κB 经典通路。在携带 FFMA-AML 细胞并用 3-Cl-AHPC 或 AHP3 处理的 NOD-SCID 小鼠和携带 TF(v-SRC) 细胞并用 AHP3 处理的 SCID 小鼠中观察到存活率显着延长。我们之前已经证明，ARR 与孤儿核受体小异二聚体伴侣 (SHP) 结合，并且 SHP 的表达是 ARR 介导的细胞凋亡所必需的。这些 AML 细胞中 SHP 的诱导缺失会阻断 3-Cl-AHPC 和 AHP3 介导的细胞凋亡诱导。这些结果支持进一步开发 3-Cl-AHPC 和 AHP3 作为治疗 AML 患者的潜在治疗剂。
The adamantyl-substituted retinoid-related compounds, 3-Cl-AHPC and AHP3 induce apoptosis in vitro and in vivo in a newly established human AML cell line, FFMA-AML and in the established TF(v-SRC) AML cell line. FFMA-AML and TF(v-SRC) cells displayed resistance to the standard retinoids- (including trans retinoic acid, 9 cis retinoic acid and the synthetic retinoid TTNPB) mediated apoptosis but sensitivity to 3-Cl-AHPC- and AHP3- mediated apoptosis in vitro and in vivo as documented by PARP cleavage and apoptosis TUNEL assay. 3-Cl-AHPC or AHP3 exposure in vitro resulted in decreased expression of the anti-apoptotic proteins (c-IAP1, XIAP) and phospho-Bad and activated the NF-κB canonical pathway. A significant prolongation of survival was observed in both NOD-SCID mice carrying FFMA-AML cells and treated with either 3-Cl-AHPC or AHP3 and SCID mice carrying TF(v-SRC) cells and treated with AHP3. We have previously shown that ARRs bind to the orphan nuclear receptor small heterodimer partner (SHP) and that the expression of SHP is required for ARR-mediated apoptosis. Induced loss of SHP in these AML cells blocked 3-Cl-AHPC- and AHP3-mediated induction of apoptosis. These results support the further development of 3-Cl-AHPC and AHP3 as potential therapeutic agents in the treatment of AML patients.