急性髓系白血病细胞对三萜类化合物CDDO-咪唑化物的耐药性与低水平的半胱天冬酶-8和FADD有关。

Resistance of acute myeloid leukemic cells to the triterpenoid CDDO-Imidazolide is associated with low caspase-8 and FADD levels.

作者信息

Riccioni Roberta, Senese Mara, Diverio Daniela, Riti Viviana, Mariani Gualtiero, Boe Alessandra, LoCoco Francesco, Foà Robin, Peschle Cesare, Sporn Michael, Testa Ugo

机构信息

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

出版信息

Leuk Res. 2008 Aug;32(8):1244-58. doi: 10.1016/j.leukres.2007.12.008. Epub 2008 Mar 4.

DOI:10.1016/j.leukres.2007.12.008

PMID:18304628

Abstract

The synthetic triterpenoid CDDO-Im-induced apoptosis of patient-derived AML blasts: 11/25 AMLs were highly sensitive, while the remaining were moderately sensitive to CDDO-Im. The addition of TRAIL significantly potentiated the cytotoxic effect of CDDO-Im, through mechanisms involving the induction of TRAIL-R1/TRAIL-R2 and downmodulation of TRAIL-R3/TRAIL-R4. Biochemical studies showed that CDDO-Im: induced a rapid and marked GSH depletion and antioxidants (GSH or NAC) completely inhibited its pro-apoptotic effect; sequentially activated caspase-8, -9 and -3; caspase inhibitors partially protected AML blasts from CDDO-Im-induced apoptosis; resistance of AML blasts to CDDO-Im-induced apoptosis correlated with low caspase-8/FADD and high Bcl-X(L) expression in leukemic blasts.

摘要

合成三萜类化合物CDDO-Im诱导患者来源的急性髓系白血病（AML）原始细胞凋亡：25例AML中有11例对CDDO-Im高度敏感，其余对CDDO-Im中度敏感。加入肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过涉及诱导TRAIL-R1/TRAIL-R2和下调TRAIL-R3/TRAIL-R4的机制显著增强了CDDO-Im的细胞毒性作用。生化研究表明，CDDO-Im：诱导谷胱甘肽（GSH）迅速且显著耗竭，抗氧化剂（GSH或N-乙酰半胱氨酸）完全抑制其促凋亡作用；依次激活半胱天冬酶-8、-9和-3；半胱天冬酶抑制剂部分保护AML原始细胞免受CDDO-Im诱导的凋亡；AML原始细胞对CDDO-Im诱导凋亡的抗性与白血病原始细胞中低水平的半胱天冬酶-8/FADD和高水平的Bcl-X(L)表达相关。