Department of Hepato-biliary-pancreatic Surgery, The Second Affiliated Hospital of Wenzhou Medical College, No. 109, West Xue-yuan Road, Wenzhou 325027, P.R. China.
Int J Oncol. 2011 Dec;39(6):1381-90. doi: 10.3892/ijo.2011.1147. Epub 2011 Jul 29.
Pancreatic adenocarcinoma is one of the most common malignancies worldwide. Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine can induce activation of Akt and nuclear factor-κB (NF-κB), which is associated with its chemoresistance. It has been reported that gemcitabine combination therapies result in improved survival outcomes in pancreatic cancer. Therefore, agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Emodin is an active component of Chinese medicinal herbs and can inhibit the activation of Akt and NF-κB. In this study, we investigated whether emodin could enhance the anticancer effect of gemcitabine on pancreatic cancer in vivo. We demonstrated that treatment of gemcitabine combined with emodin efficiently suppressed tumor growth in mice inoculated with pancreatic tumor cells. This treatment paradigm promoted apoptotic cell death and mitochondrial fragmentation. Furthermore, it reduced phosphorylated-Akt (p-Akt) level, NF-κB activation and Bcl-2/Bax ratio, increased caspase-9 and -3 activation, Cytochrome C (CytC) release occurred in combination therapy. Collectively, emodin enhanced the activity of gemcitabine in tumor growth suppression via inhibition of Akt and NF-κB activation, thus promoting the mitochondrial-dependent apoptotic pathway. Therefore, our findings may provide new insights into understanding the pharmacological regulation of emodin on gemcitabine-mediated proapoptosis in pancreatic cancer and may aid in the design of new therapeutic strategies for the intervention of human pancreatic cancers.
胰腺腺癌是全球最常见的恶性肿瘤之一。吉西他滨是目前胰腺癌的标准一线化疗药物。然而，吉西他滨可以诱导 Akt 和核因子-κB（NF-κB）的激活，这与它的化疗耐药性有关。据报道，吉西他滨联合治疗可改善胰腺癌患者的生存结局。因此，需要寻找既能增强吉西他滨疗效又能克服其耐药性的药物来治疗胰腺癌。大黄素是中药的一种活性成分，能抑制 Akt 和 NF-κB 的激活。在本研究中，我们研究了大黄素是否能增强吉西他滨对体内胰腺癌的抗癌作用。结果表明，吉西他滨联合大黄素治疗能有效抑制胰腺癌细胞接种的小鼠肿瘤生长。这种治疗方案促进了细胞凋亡和线粒体碎片化。此外，它降低了磷酸化 Akt（p-Akt）水平、NF-κB 激活和 Bcl-2/Bax 比值，增加了 caspase-9 和 -3 的激活，细胞色素 C（CytC）在联合治疗中释放。总之，大黄素通过抑制 Akt 和 NF-κB 的激活增强了吉西他滨抑制肿瘤生长的活性，从而促进了线粒体依赖性凋亡途径。因此，我们的研究结果可能为理解大黄素对吉西他滨诱导的胰腺癌促凋亡的药理学调节提供新的见解，并可能有助于设计新的治疗策略来干预人类胰腺癌。
