Santidrián Antonio F, Cosialls Ana M, Coll-Mulet Llorenç, Iglesias-Serret Daniel, de Frias Mercè, González-Gironès Diana M, Campàs Clara, Domingo Alicia, Pons Gabriel, Gil Joan
Departament de Ciències Fisiològiques II, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
Haematologica. 2007 Dec;92(12):1631-8. doi: 10.3324/haematol.11194.
The potential anticancer agent 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a translocator protein (18KDa) (TSPO) ligand, facilitates the induction of cell death by a variety of cytotoxic and chemotherapeutic agents. Primary chronic lymphocytic leukemia (CLL) cells overexpress TSPO. The aim of this study was to examine the effects of PK11195 on CLL cells. Table 1. Characteristics of the patients with chronic lymphocytic leukemia.
Using cytometric analysis, we studied the cytotoxic effects of PK11195 on peripheral B and T lymphocytes from patients with CLL and from healthy donors. Western blot and cytometric analyses were used to study the mitochondrial effects of PK11195 on CLL cells. Moreover, we analyzed the cytotoxic effect of PK11195 in patients' cells with mutated p53 or ATM.
PK11195 induces apoptosis and had additive effects with chemotherapeutic drugs in primary CLL cells. Other TSPO ligands such as RO 5-4864 and FGIN-1-27 also induce apoptosis in CLL cells. PK11195 induces mitochondrial depolarization and cytochrome c release upstream of caspase activation, and dithiocyana-tostilbene-2,2- disulfonic acid (DIDS), a voltage-dependent anion channel (VDAC) inhibitor, inhibits PK11195-induced apoptosis, demonstrating a direct involvement of mitochondria. CLL cells and normal B cells are more sensitive than T cells to PK11195-induced apoptosis. Interestingly, PK11195 induced apoptosis in CLL cells irrespective of their p53 or ATM status.
These results suggest that PK11195 alone or in combination with chemotherapeutic drugs might be a new therapeutic option for the treatment of CLL.
潜在抗癌药物1-(2-氯苯基-N-甲基丙基)-3-异喹啉甲酰胺（PK11195）是一种转位蛋白（18 kDa）（TSPO）配体，可促进多种细胞毒性和化疗药物诱导细胞死亡。原发性慢性淋巴细胞白血病（CLL）细胞过度表达TSPO。本研究旨在探讨PK11195对CLL细胞的影响。表1.慢性淋巴细胞白血病患者的特征。
通过细胞计数分析，我们研究了PK11195对CLL患者及健康供体外周B淋巴细胞和T淋巴细胞的细胞毒性作用。采用蛋白质免疫印迹法和细胞计数分析研究PK11195对CLL细胞的线粒体效应。此外，我们分析了PK11195对p53或ATM突变患者细胞的细胞毒性作用。
PK11195可诱导原发性CLL细胞凋亡，并与化疗药物产生协同作用。其他TSPO配体如RO 5-4864和FGIN-1-27也可诱导CLL细胞凋亡。PK11195在半胱天冬酶激活上游诱导线粒体去极化和细胞色素c释放，而电压依赖性阴离子通道（VDAC）抑制剂二硫氰基苯乙烯-2,2-二磺酸（DIDS）可抑制PK11195诱导的凋亡，表明线粒体直接参与其中。CLL细胞和正常B细胞比T细胞对PK11195诱导的凋亡更敏感。有趣的是，无论p53或ATM状态如何，PK11195均可诱导CLL细胞凋亡。
这些结果表明，PK11195单独或与化疗药物联合使用可能是治疗CLL的一种新的治疗选择。
