International Journal of Cancer Journal International Du Cancer, 2011, 128(5):1240-50.

Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo

Sanjeev Banerjee, Dejuan Kong, Asfar S Azmi, et al

Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Wayne State University, Detroit, MI, USA.

Oxaliplatin (OxP) has been used in combination therapy with gemcitabine for the treatment of pancreatic cancer (PC), but the beneficial effect was marginal, which is believed to be due to de novo and acquired drug resistance of PC. Here, we report our in vitro and in vivo preclinical evidence in support of chemosensitization of drug-resistant cells by a nontoxic chemopreventive agent (genistein). Genistein pretreatment together with low concentration of OxP showed significant reduction in cell viability and colony formation concomitant with increased apoptosis (p < 0.01), which was highly synergistic. Drug resistance of PC is allegedly linked with both constitutive and OxP-induced activation of NF-κB, and we found that inactivation of (nuclear factor kappa B) NF-κB by genistein before treatment of cells with OxP was required for cell killing, which was consistent with the downregulation of NF-κB and its downstream antiapoptotic genes (Bcl-2, XIAPs and survivin). Most importantly, our in vivo experiments using orthotopic mouse model showed significant reduction in tumor size (p < 0.01) and reduction of locoregional lymph node metastasis by combination treatment. These results were also consistent with inactivation of NF-κB and the downregulation of NF-κB downstream genes, decreased proliferation marker (Ki-67) and increased apoptosis (TUNEL) in tumor remnants, all of which was consistent with in vitro findings. From these results, we conclude that genistein sensitizes drug-resistant PC to OxP, which is mechanistically linked with inactivation of NF-κB signaling, resulting in greater antitumor effects, and thus our data suggest that this approach could be useful in improving the treatment outcome for patients diagnosed with PC.

美国《国际癌症杂志》，2011年3月

在体外和体内通过一种新方法使抗吉西他滨的胰腺癌细胞恢复对奥沙利铂的敏感性

桑吉 巴纳吉，德胡安 孔，阿斯法 S 阿兹米等

美国韦恩州立医科大学芭芭拉安卡马诺斯癌症研究所病理学部

奥沙利铂 (OxP)和吉西他滨被用于联合化疗治疗胰腺癌 (PC)，但是其有益效果甚微，认为是由于乳腺癌具有获得性耐药性。这里，我们报道了在体内和体外的临床证据通过无毒的化学预防试剂 （金雀异黄素）使耐药细胞产生化学敏感性。与低浓度的 OxP联合金雀异黄素预处理结果在细胞活力和集落形成方面表现出显著减少，同时细胞凋亡有所增加 (p < 0.01)，这一点高度协同。PC的耐药性据称与构造性和 OxP 诱导 NF-κB 的活化有关，并且我们发现在用OxP处理细胞之前由金雀异黄素造成的（核转录因子 κB）NF-κB的失活被用于细胞灭杀，这一点与NF-κB及其下游抗凋亡基因 （Bcl-2、 XIAPs 和存活素）的下调相符。最重要的是，我们的体内实验中使用的原位小鼠模型通过联合治疗后表现出肿瘤尺寸明显减小 (p < 0.01) 并且局部淋巴结转移减弱。这些结果也符合肿瘤遗留物中NF-κB 的失活和NF-κB下游基因的下调，扩散标记 (Ki-67) 减少和细胞凋亡的增加 (TUNEL)，所有的表现与体外研究结果相一致。从这些结果，我们可以得出结论染料木黄酮可以使耐药性胰腺癌对OxP敏感，这与NF-κ B 信号的失活机理性相关，造成更大的抗肿瘤作用，因此我们的数据表明这种方法可能有助于诊断为胰腺癌的病人改善治疗结果。