Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Department of Central Laboratory of Blood Cancer, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Biochem Pharmacol. 2014 Apr 1;88(3):322-33. doi: 10.1016/j.bcp.2014.01.041. Epub 2014 Feb 9.
Although gemcitabine is currently the best chemotherapeutic agent available for the treatment of advanced pancreatic cancer, eventual failure of response is a significant clinical problem. Therefore, novel therapeutic approaches against this disease are highly needed. The aim of this study was to evaluate whether shikonin, a naphthoquinone derivative, has potential in the treatment of pancreatic cancer when used either alone or in combination with gemcitabine. Our in vitro results showed that shikonin inhibited the proliferation of three different human pancreatic cancer cell lines and potentiated the cytotoxic effect of gemcitabine, which correlated with the down-regulation of constitutive as well as gemcitabine-induced activation of NF-κB and NF-κB-regulated gene products. Most importantly, using a xenograft model of human pancreatic cancer, we found shikonin alone significantly suppressed tumor growth and argumented the antitumor activity of gemcitabine. These effects also correlated with the down-regulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that shikonin can suppress the growth of human pancreatic tumors and potentiate the antitumor effects of gemcitabine through the suppression of NF-κB and NF-κB-regulated gene products.
虽然吉西他滨是目前治疗晚期胰腺癌的最佳化疗药物，但最终的治疗失败仍是一个严重的临床问题。因此，迫切需要针对这种疾病的新的治疗方法。本研究旨在评估紫草素（一种萘醌衍生物）单独或联合吉西他滨治疗胰腺癌的潜力。我们的体外实验结果表明，紫草素能抑制三种不同的人胰腺癌细胞系的增殖，并增强吉西他滨的细胞毒性作用，这与 NF-κB 的组成性激活及其调控基因产物的诱导激活的下调相关。最重要的是，利用人胰腺癌细胞的异种移植模型，我们发现紫草素单独使用就能显著抑制肿瘤生长，并增强吉西他滨的抗肿瘤活性。这些作用还与 NF-κB 活性及其靶基因的下调、增殖（PCNA 和 Ki-67）的减少、微血管密度（CD31）的减少和肿瘤残余物中凋亡（TUNEL）的增加相关。总之，我们的结果表明，紫草素可以通过抑制 NF-κB 和 NF-κB 调控的基因产物来抑制人胰腺肿瘤的生长，并增强吉西他滨的抗肿瘤作用。
