Riordan F A, Bravery C A, Mengubas K, Ray N, Borthwick N J, Akbar A N, Hart S M, Hoffbrand A V, Mehta A B, Wickremasinghe R G
Department of Hematology, Royal Free Hospital School of Medicine, London, UK.
Oncogene. 1998 Mar 26;16(12):1533-42. doi: 10.1038/sj.onc.1201680.
Philadelphia chromosome (Ph)-positive leukaemia cells express the chimeric bcr/abl oncoprotein, whose deregulated protein tyrosine kinase (PTK) activity antagonizes the induction of apoptosis by DNA damaging agents. Treatment of Ph-positive K562, TOM 1 and KCL-22 cells with etoposide for 2d induced cytosolic vacuolation, but not nuclear condensation or DNA fragmentation. The bcr/abl kinase-selective inhibitor herbimycin A increased the induction of nuclear apoptosis by etoposide or gamma-radiation. The concentration of herbimycin required to synergize with etoposide was similar to that required to decrease the level of tyrosine phosphorylated proteins or of the protein tyrosine kinase activity of anti-abl immune complexes in K562 cells. The ability of herbimycin A to sensitize K562, TOM 1 or KCL-22 cells to apoptosis induction correlated with its ability to decrease the cellular content of phosphotyrosyl proteins in these Philadelphia-positive lines. Enhancement of nuclear apoptosis by herbimycin was not attributable to downregulation of the bcl-2 or bcl-XL anti-apoptotic proteins. In contrast, herbimycin protected Philadelphia-negative HL60 cells from apoptosis induction by etoposide and did not affect killing of NC37 and CEM cells. The data suggest that the induction of apoptosis is blocked in cells expressing the bcr/abl oncoprotein and that herbimycin A increases induction of programmed cell death following DNA damage. Selective PTK inhibitors may therefore be of value in securing the genetic death of Ph-positive leukaemia cells.
费城染色体（Ph）阳性白血病细胞表达嵌合的bcr/abl癌蛋白，其失调的蛋白酪氨酸激酶（PTK）活性可拮抗DNA损伤剂诱导的细胞凋亡。用依托泊苷处理Ph阳性的K562、TOM 1和KCL-22细胞2天可诱导胞质空泡化，但不会诱导核浓缩或DNA片段化。bcr/abl激酶选择性抑制剂赫曲霉素A增强了依托泊苷或γ射线诱导的核凋亡。与依托泊苷协同作用所需的赫曲霉素浓度与降低K562细胞中酪氨酸磷酸化蛋白水平或抗abl免疫复合物的蛋白酪氨酸激酶活性所需的浓度相似。赫曲霉素A使K562、TOM 1或KCL-22细胞对凋亡诱导敏感的能力与其降低这些费城染色体阳性细胞系中磷酸酪氨酸蛋白细胞含量的能力相关。赫曲霉素对核凋亡的增强作用并非归因于抗凋亡蛋白bcl-2或bcl-XL的下调。相反，赫曲霉素可保护费城染色体阴性的HL60细胞免受依托泊苷诱导的凋亡，且不影响NC37和CEM细胞的杀伤。数据表明，在表达bcr/abl癌蛋白的细胞中，细胞凋亡的诱导被阻断，且赫曲霉素A可增加DNA损伤后程序性细胞死亡的诱导。因此，选择性PTK抑制剂可能对确保Ph阳性白血病细胞的基因死亡有价值。
