John D. Dingell VA Medical Center, Wayne State University, Karmanos Cancer Institute, Oncology 11M-HO, Room C3540, 4646 John R. Street, Detroit, MI 48201, USA.
Mol Cancer Ther. 2010 Nov;9(11):2903-13. doi: 10.1158/1535-7163.MCT-10-0546. Epub 2010 Nov 9.
The adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 induce apoptosis in vitro and in vivo in a newly established human acute myelogenous leukemia (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 apoptosis mediated by the standard retinoids (including trans-retinoic acid, 9-cis-retinoic acid, and the synthetic retinoid TTNPB) but showed sensitivity to apoptosis mediated by 3-Cl-AHPC- and AHP3 in vitro and in vivo as documented by poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. 3-Cl-AHPC or AHP3 exposure in vitro resulted in decreased expression of the antiapoptotic proteins (cellular inhibitor of apoptosis 1, X-linked inhibitor of apoptosis protein) and phospho-Bad and activated the NF-κB canonical pathway. A significant prolongation of survival was observed both in nonobese diabetic severe combined immunodeficient mice carrying FFMA-AML cells and treated with either 3-Cl-AHPC or AHP3 and in severe combined immunodeficient 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.
adamantyl 取代的视黄醇相关（ARR）化合物 3-Cl-AHPC 和 AHP3 在新建立的人急性髓系白血病（AML）细胞系 FFMA-AML 和已建立的 TF(v-SRC)AML 细胞系中诱导体外和体内的细胞凋亡。FFMA-AML 和 TF(v-SRC)细胞对标准视黄醇（包括反式维甲酸、9-顺维甲酸和合成视黄醇 TTNPB）介导的凋亡具有抗性，但对 3-Cl-AHPC 和 AHP3 在体外和体内介导的凋亡敏感，如多聚（ADP-核糖）聚合酶（PARP）切割和凋亡末端脱氧核糖核苷酸转移酶介导的 dUTP 缺口末端标记检测所证明的那样。体外暴露于 3-Cl-AHPC 或 AHP3 导致抗凋亡蛋白（细胞凋亡抑制剂 1、X 连锁凋亡抑制剂蛋白）和磷酸化 Bad 的表达减少，并激活 NF-κB 经典途径。在携带 FFMA-AML 细胞并接受 3-Cl-AHPC 或 AHP3 治疗的非肥胖糖尿病严重联合免疫缺陷小鼠和携带 TF(v-SRC)细胞并接受 AHP3 治疗的严重联合免疫缺陷小鼠中，均观察到生存时间显著延长。我们之前已经表明，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 介导的凋亡所必需的。在这些 AML 细胞中诱导 SHP 缺失阻止了 3-Cl-AHPC 和 AHP3 介导的凋亡诱导。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。
