Cancer Biomarkers and Prevention Group, Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, United Kingdom.
Int J Cancer. 2011 Jul 15;129(2):476-86. doi: 10.1002/ijc.25670. Epub 2010 Nov 3.
The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki-67, cleaved caspase-3 and Notch-1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin-resistant p53 wildtype and p53(-/-) cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle-treated animals was 53, 35 and 16%, respectively. Ki-67 and Notch-1 immunoreactivity was decreased by the combination when compared to vehicle-treated animals, with cleaved caspase-3 rising by 4.4-fold. Meriva did not adversely affect the DNA-platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin-based chemotherapy regimens has the potential for clinical benefit.
本研究旨在确定奥沙利铂与姜黄素联合用药在体外奥沙利铂耐药细胞系中的效力，并评估新型姜黄素制剂（Meriva®）单独用药以及联合奥沙利铂在结直肠荷瘤小鼠中的疗效，探索体内相关药效学标志物。本研究中，我们构建了奥沙利铂耐药的 HCT116 p53wt 和 p53(-/-)细胞系，并研究了奥沙利铂与姜黄素联合用药对耐药性和增殖相关蛋白的影响。将 HCT116 p53wt 结直肠癌细胞植入 80 只裸鼠体内，然后将其随机分为以下治疗组：对照组；Meriva 组；奥沙利铂组；Meriva+奥沙利铂组。评估肿瘤体积，并检测 Ki-67、cleaved caspase-3 和 Notch-1 的表达。结果显示，与奥沙利铂单药相比，姜黄素联合奥沙利铂能够更有效地降低奥沙利铂耐药 p53 野生型和 p53(-/-)细胞系的增殖能力，同时降低与增殖相关的标志物。在异种移植模型中治疗 21 天后，疗效的顺序为联合用药组＞Meriva 组＞奥沙利铂组＞对照组。与对照组相比，奥沙利铂联合用药组的肿瘤体积分别减少了 53%、35%和 16%。与对照组相比，联合用药组 Ki-67 和 Notch-1 的免疫反应性降低，cleaved caspase-3 升高了 4.4 倍。Meriva 不会影响奥沙利铂的 DNA 烷化能力。在奥沙利铂耐药的体外模型中，姜黄素增强了奥沙利铂的细胞毒性。在体内，Meriva 大大增强了奥沙利铂的疗效，而不影响奥沙利铂的作用模式。在奥沙利铂为基础的化疗方案中加入配方姜黄素可能具有临床获益。
