INSERM UMR 895, Team 2: Cell Death Differentiation and Cancer, Nice, France.
PLoS One. 2009 Nov 18;4(11):e7889. doi: 10.1371/journal.pone.0007889.
CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.
CML 是一种造血干细胞疾病，其特征在于 t(9;22) (q34;q11) 易位编码致癌蛋白 p210BCR-ABL。研究了具有已知抗白血病作用的化合物腺苷酸（AICAR，5-氨基咪唑-4-羧酰胺-1-β-D-核糖呋喃苷）对 B 细胞慢性淋巴细胞白血病（B-CLL）的影响在不同的 CML 细胞系中。腺苷酸触发了 K562、LAMA-84 和 JURL-MK1 的细胞代谢丧失，并且对携带 T315I-BCR-ABL 突变的伊马替尼耐药 K562 细胞和 Ba/F3 细胞也有效。腺苷酸的抗白血病作用不涉及细胞凋亡，而是需要诱导自噬性细胞死亡。Sh-RNA 的 AMPK 敲低未能阻止腺苷酸的作用，表明这是一种 AMPK 非依赖性机制。GF109203X 和 Ro-32-0432 均可抑制经典和新型 PKC，均可阻断腺苷酸的作用，因此，腺苷酸可触发 K562 细胞中几种 PKC 同工型的重定位和激活。此外，该化合物在甲基纤维素中的 CML 细胞集落形成试验和裸鼠中 K562 细胞的异种移植模型中均表现出强大的抗白血病作用。总之，我们的工作确定了一种原始而意外的机制，即通过 PKC 激活，腺苷酸触发自噬性细胞死亡。因此，除了在 B-CLL 中具有广阔的应用前景外，腺苷酸对伊马替尼耐药的 CML 患者也可能有益。
