A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- and Bcl-2-independent mechanism
A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- and Bcl-2-independent mechanism
复制标题
DOI：
10.1182/blood-2004-05-1957
复制
发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Byrd, JC
中科院分区：
文献类型：
--
作者：
Johnson, AJ;Smith, LL;Byrd, JC
慢性淋巴细胞白血病（CLL）是一种以细胞凋亡破坏为特征的不可治愈的成人白血病。OSU 03012是一种生物可利用的第三代塞来昔布衍生物，不具有环氧合酶-2抑制活性，可有效诱导前列腺癌细胞系凋亡，目前正在美国国家癌症研究所（NCI）快速干预开发（RAID）计划中开发为抗癌疗法。我们评估了OSU 03012诱导原代CLL细胞凋亡的能力及其发生机制。OSU 03012在24小时的LC 50（致死浓度50%）为7.1 μ M，在72小时降低至5.5 μ M。此外，我们已经证明OSU 03012通过激活细胞凋亡的内在线粒体途径介导细胞凋亡，但也激活非半胱天冬酶依赖的替代细胞死亡途径。半胱天冬酶依赖性和非依赖性细胞凋亡途径的早期激活对OSU 03012来说是新颖的，并表明它对治疗CLL具有巨大的潜在前景。此外，与大多数用于治疗白血病或其他形式癌症的治疗剂不同，OSU 03012诱导细胞死亡完全不依赖于bcl-2表达。总之，这些数据为OSU 03012作为CLL潜在治疗药物的进一步临床前开发提供了依据。(c)2065美国血液学会
Chronic lymphocytic leukemia (CLL) is an incurable adult leukemia characterized by disrupted apoptosis. OSU03012 is a bioavailable third-generation celecoxib derivative devoid of cyclooxygenase-2 inhibitory activity that potently induces apoptosis in prostate cancer cell lines and is being developed as an anticancer therapy in the National Cancer Institute (NCI) Rapid Access to Intervention Development (RAID) program. We assessed the ability of OSU03012 to induce Apoptosis in primary CLL cells and the mechanism by which this occurs. The LC50 (lethal concentration 50%) of OSU03012 at 24 hours was 7.1 mu M, and this decreased to 5.5 mu M at 72 hours. Additionally, we have demonstrated that OSU03012 mediates apoptosis by activation of the intrinsic, mitochondrial pathway of apoptosis but also activates alternative cell death pathways that are caspase independent. The early activation of both caspase-dependent and -independent pathways of apoptosis is novel to OSU03012 and suggests it has great potential promise for the treatment of CLL. Moreover, unlike the great majority of therapeutic agents used to treat leukemia or other forms of cancer, OSU03012 induces cell death entirely independent of bcl-2 expression. Overall, these data provide justification for further preclinical development of OSU03012 as a potential therapeutic agent for CLL. (c) 2065 by The American Society of Hematology