Effects of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantane (DPD), a reactive oxygen species and apoptosis inducing agent, on human leukemia cells in vitro and in vivo
Effects of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantane (DPD), a reactive oxygen species and apoptosis inducing agent, on human leukemia cells in vitro and in vivo
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DOI：
10.1016/j.taap.2004.06.013
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发表时间：
2005-01-01
影响因子：
3.8
通讯作者：
Wang, JJ
中科院分区：
文献类型：
--
作者：
Chang, YF;Chi, CW;Wang, JJ
1，6-双[4-（4-氨基-3-羟基苯氧基）苯基]金刚烷（DPD）是一种新型的细胞生长抑制剂和分化诱导剂，在美国国家癌症研究所（NCI）的抗癌药物筛选系统中被发现对多种肿瘤细胞具有生长抑制作用。以前，我们证明了DPD在体外和体内都抑制人结肠癌细胞系的生长。在这项研究中，我们研究了DPD对两种人白血病细胞系的抗癌作用。DPD在体外对两种人白血病细胞系，早幼粒细胞系HL-60和淋巴母细胞系Molt-3产生生长抑制活性。在小鼠异种移植物中也观察到DPD抑制肿瘤生长的体内效果。在“严重联合免疫缺陷”（SCID）小鼠中每周两次腹膜内激发DPD后，未观察到急性毒性。体外实验表明，HL-60细胞对DPD的敏感性高于Molt-3细胞，诱导细胞周期阻滞于G（0）/G（1）期，并出现亚二倍体DNA片段。在DPD处理的细胞凋亡之前，超氧化物（O-2（-））的增加、线粒体膜电位的耗散、半胱天冬酶3的活化和膜联蛋白V结合的增加是明显的。超氧化物歧化酶1（SODI）mRNA表达在DPD处理的HL-60和Molt-3细胞中也降低。因此，SOD的抑制可能是DPD处理细胞产生超氧化物的主要原因，伴随着H2 O2的减少。抗氧化剂的加入可以减少DPD诱导的HL-60细胞线粒体损伤、caspase激活和annexin V结合。结果提示，细胞内O-2（-）的产生在DPD介导的HL-60细胞生长停滞和凋亡的启动和协调中起作用。重要的是，添加三氧化二砷，一种能够产生活性氧（ROS）的化合物，显着增强了DPD的体外活性。这些结果表明，DPD似乎是一个潜在的新模式，在人类白血病的治疗。(C)2004爱思唯尔公司All rights reserved.
1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantine (DPD), a new cytostatic and differentiation inducing agent, was found to inhibit the growth of several cancer cell lines in the National Cancer Institute (NCI) Anticancer Drug Screen system. Previously, we demonstrated that DPD inhibited the growth of human colon cancer cell lines both in vitro and in vivo. In this study, we examined the anticancer effects of DPD on two human leukemia cells lines. DPD exerted growth inhibitory activities in vitro against two human leukemia cell lines, the promyeloid line HL-60 and the lymphoblastic line Molt-3. The in vivo effect of tumor growth suppression by DPD was also observed in mouse xenografts. No acute toxicity was observed after an intra-peritoneal challenge of DPD in "severe combined immune-deficiency" (SCID) mice twice a week. The in vitro study showed HL-60 was more sensitive to DPD than Molt-3 through induction of G(0)/G(1) cell-cycle arrest with the appearance of a hypodiploid DNA fraction. The increased superoxide (O-2(-)), dissipation of the mitochondrial membrane potential, activation of caspase 3, and increase in annexin V binding were evident before apoptosis in DPD-treated cells. The superoxide dismutase 1 (SODI) mRNA expression was also decreased in DPD-treated HL-60 and Molt-3 cells. Thus, it appeared that inhibition of SOD might be the major cause for the production of cellular superoxide with concomitant decrease of H2O2 in DPD-treated cells. Addition of antioxidant can reduce DPD-induced mitochondrial damage, caspase activation, and annexin V binding in HL-60 cells. The results suggest that the cellular generation of O-2(-) plays a role in initiating and coordinating DPD-mediated growth arrest and apoptosis of HL-60 cells. Importantly, addition of arsenic trioxide, a compound capable of reactive oxygen species (ROS) generation, significantly enhanced the in vitro activity of DPD. These results suggest that DPD appears to be a potential new modality in human leukemia therapy. (C) 2004 Elsevier Inc. All rights reserved.