Triptolide augments the effects of 5-lipoxygenase RNA interference in suppressing pancreatic tumor growth in a xenograft mouse model
Triptolide augments the effects of 5-lipoxygenase RNA interference in suppressing pancreatic tumor growth in a xenograft mouse model
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雷公藤内酯醇增强 5-脂氧合酶 RNA 干扰抑制异种移植小鼠模型胰腺肿瘤生长的作用
DOI：
10.1007/s00280-011-1698-5
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发表时间：
2012-01-01
影响因子：
3
通讯作者：
Zhou, Guoxiong
中科院分区：
文献类型：
--
作者：
Ding, Xiaoling;Zhou, Xiaorong;Zhou, Guoxiong
胰腺癌是所有癌症中死亡率最高的癌症之一，需要新的策略或试剂来应对这种疾病。雷公藤内酯醇（TL）在体外能有效抑制胰腺癌细胞的生长。另一方面，阻断5-LOX通路可能有助于胰腺癌的治疗。在本研究中，我们测试了5-LOX RNA干扰和TL单独或联合抑制人胰腺癌生长在异种移植小鼠模型中的效果。5-LOX短发夹RNA（shRNA）载体的开发和筛选出其在人胰腺癌细胞株SW 1990的体外疗效。通过测定细胞增殖和凋亡来评价它们的抗肿瘤作用。单独或与TL组合给予有效的5-LOX shRNA以治疗胰腺肿瘤异种移植物。Western blotting和免疫组化检测5-LOX和VEGF的表达水平，体外敲除5-LOX基因抑制癌细胞生长，体内转染5-LOX shRNA抑制移植瘤生长。TL治疗诱导肿瘤抑制，并大大增强了5-LOX shRNA在小鼠模型中的抗肿瘤作用。5-LOX RNA干扰或TL治疗抑制肿瘤组织VEGF的表达，联合治疗进一步降低VEGF的表达，两种方法在体内均具有抗肿瘤作用，联合使用两种方法具有更强的抗肿瘤作用。联合治疗对VEGF表达的协同作用可能是其强抗肿瘤作用的机制之一。
Pancreatic cancer has one of the highest fatality rates of all cancers, and new strategies or reagents to tackle this disease are needed. Triptolide (TL) is able to potently inhibit the growth of pancreatic tumor cells in vitro. On the other hand, blockage of 5-LOX pathway might be useful for treatment of pancreatic cancer. In the current study, we tested the effects of 5-LOX RNA interference and TL individually or in combination in suppressing human pancreatic tumor growth in xenograft mouse model.5-LOX short hairpin RNA (shRNA) vectors were developed and screened out for their efficacy in human pancreatic cancer cell line SW1990 in vitro. Their antitumor effects were also evaluated by measuring cell proliferation and apoptosis. An effective 5-LOX shRNA was given alone or in combination with TL to treat pancreatic tumor xenograft. Expression levels of 5-LOX and VEGF were measured with Western blotting and immunohistology.Knocking down 5-LOX gene suppressed cancer cell growth in vitro and intra-tumoral delivering of 5-LOX shRNA inhibited growth of transplanted tumor in vivo. TL treatment induced tumor suppression and greatly enhanced antitumor effects of 5-LOX shRNA in the mouse model. 5-LOX RNA interference or TL treatment suppresses VEGF expression in tumor tissue, and combined treatment further reduces its expression.Both treatments exerted antitumor effects in vivo, and combined use of the two approaches produced more powerful antitumor effects. Synergistic effects of combined treatment in VEGF expression may contribute to the mechanisms of the strong antitumor effects.