Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nangtong, Jiangsu, People's Republic of China.
Cancer Chemother Pharmacol. 2012 Jan;69(1):253-61. doi: 10.1007/s00280-011-1698-5. Epub 2011 Jun 29.
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.
胰腺癌是所有癌症中死亡率最高的癌症之一，因此需要新的策略或试剂来解决这一疾病。雷公藤内酯醇（TL）能够在体外强力抑制胰腺肿瘤细胞的生长。另一方面，阻断 5-LOX 途径可能对治疗胰腺癌有用。在本研究中，我们测试了单独或联合使用 5-LOX RNA 干扰和 TL 在抑制异种移植小鼠模型中人类胰腺肿瘤生长方面的效果。
开发了 5-LOX 短发夹 RNA（shRNA）载体，并在体外筛选出人胰腺癌细胞系 SW1990 中的有效性。还通过测量细胞增殖和凋亡来评估它们的抗肿瘤作用。将有效的 5-LOX shRNA 单独或与 TL 联合用于治疗胰腺肿瘤异种移植。通过 Western 印迹和免疫组织化学测量 5-LOX 和 VEGF 的表达水平。
敲低 5-LOX 基因抑制了体外癌细胞的生长，并且肿瘤内递送 5-LOX shRNA 抑制了体内移植瘤的生长。TL 治疗诱导肿瘤抑制，并大大增强了该小鼠模型中 5-LOX shRNA 的抗肿瘤作用。5-LOX RNA 干扰或 TL 治疗抑制肿瘤组织中 VEGF 的表达，联合治疗进一步降低其表达。
两种治疗方法均在体内发挥抗肿瘤作用，联合使用两种方法产生更强的抗肿瘤作用。联合治疗在 VEGF 表达方面的协同作用可能是其强大抗肿瘤作用的机制之一。
