Wun Ted, McKnight Hayes, Tuscano Joseph M
Department of Internal Medicine, Division of Hematology and Oncology, UC Davis Cancer Center, University of California, 4501 X Street, Sacramento, CA 95817, USA.
Leuk Res. 2004 Feb;28(2):179-90. doi: 10.1016/s0145-2126(03)00183-8.
B cell lymphomas are a diverse group of clinicopathologic diseases with an increasing incidence. As with other malignancies, the accumulation of genetic abnormalities are required for malignant transformation of human lymphocytes. Cyclooxygenase-2 (COX-2) is a key biosynthetic enzyme in prostaglandin synthesis and has been implicated in the pathogenesis of numerous malignancies including colon, breast, and lung cancer. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In this study, several B lymphoma cell lines and primary B cells obtained from normal volunteer controls were examined for COX-2 protein expression. Immunoblot analysis demonstrated between an approximately 2.2-4.3-fold increase in COX-2 protein expression relative to primary B cells in all lymphoma cell lines examined. Increased COX-2 phosphorylation was found in the BJAB, BL41, and Raji cells whereas the levels in Daudi, Namalwa, and Ramos did not differ from that of primary B cells. Treatment with 25-100 microM celecoxib (CEL) resulted in decreased proliferation as measured by [3H]thymidine in all cell lines examined, and the effect was dose-dependent, and not significantly enhanced by chlorambucil (CHL). The effect of COX-2 inhibition on apoptosis in lymphoma cells was examined and revealed apoptotic induction of greater than 85% in all cell lines examined at 50 microM celecoxib. The pro-apoptotic effect was dose-dependent, and was not significantly enhanced by chlorambucil. Examination of apoptosis-related proteins by immunoblot analysis revealed levels of BCL-2, BCL-X(L), and Bax to be unaffected by celecoxib. In contrast, levels of Akt, MCL-1, and phosphorylated SAP-kinase were all decreased after incubation with 50 microM celecoxib. These findings suggest that increased COX-2 expression and activity, contributes to the pathogenesis of B cell lymphomas and point to a possible role for COX-2 inhibition in their treatment.
B细胞淋巴瘤是一组临床病理特征多样且发病率不断上升的疾病。与其他恶性肿瘤一样，人类淋巴细胞发生恶性转化需要积累遗传异常。环氧合酶-2（COX-2）是前列腺素合成中的关键生物合成酶，并且与包括结肠癌、乳腺癌和肺癌在内的多种恶性肿瘤的发病机制有关。关于COX-2在淋巴瘤发病机制中的潜在作用的数据很少。在本研究中，检测了几种B淋巴瘤细胞系以及从正常志愿者对照获得的原代B细胞中COX-2蛋白的表达。免疫印迹分析表明，在所检测的所有淋巴瘤细胞系中，相对于原代B细胞，COX-2蛋白表达增加了约2.2至4.3倍。在BJAB、BL41和Raji细胞中发现COX-2磷酸化增加，而Daudi、Namalwa和Ramos细胞中的水平与原代B细胞没有差异。用25至100微摩尔塞来昔布（CEL）处理导致所有检测细胞系中通过[3H]胸苷测量的增殖减少，且该效应呈剂量依赖性，苯丁酸氮芥（CHL）未显著增强该效应。研究了COX-2抑制对淋巴瘤细胞凋亡的影响，发现在50微摩尔塞来昔布时，所有检测细胞系中的凋亡诱导率均大于85%。促凋亡作用呈剂量依赖性，苯丁酸氮芥未显著增强该作用。通过免疫印迹分析检测凋亡相关蛋白发现，BCL-2、BCL-X(L)和Bax的水平不受塞来昔布影响。相反，在与50微摩尔塞来昔布孵育后，Akt、MCL-1和磷酸化SAP激酶的水平均降低。这些发现表明，COX-2表达和活性增加有助于B细胞淋巴瘤的发病机制，并指出COX-2抑制在其治疗中可能发挥的作用。
