Curcumin Regulates Colon Cancer by Inhibiting P-Glycoprotein in In-situ Cancerous Colon Perfusion Rat Model
Curcumin Regulates Colon Cancer by Inhibiting P-Glycoprotein in In-situ Cancerous Colon Perfusion Rat Model
复制标题
姜黄素通过抑制原位癌性结肠灌注大鼠模型中的 P-糖蛋白来调节结肠癌
DOI：
10.4172/1948-5956.1000221
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
J. Kanwar
中科院分区：
文献类型：
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作者：
P. Neerati;Y. A. Sudhakar;J. Kanwar
研究背景国际上对P-糖蛋白的研究主要集中在Caco-2、mdr1-LLC-PK1和mdr1-mdCK等细胞系的体外实验中，但大多数结果在体内均未能得到类似的结果。在本研究中，姜黄素对P-糖蛋白的抑制作用增加了伊立替康的通透性，因此姜黄素作为结肠癌的辅助治疗将是有益的。方法N-亚硝基-N-甲基尿素(2 mg/kg)直肠内注射诱发大鼠结肠癌。采用伊立替康大鼠结肠单次全长原位灌流模型，研究P-糖蛋白调节剂维拉帕米和姜黄素对大鼠结肠灌流的影响。将大鼠分为5组(n=6)，I组为对照组，灌流30μg/ml伊立替康、心得安和酚红。II组为N-甲基-N-亚硝基尿素诱发的癌变组。Ⅲ组：荷瘤大鼠灌胃马利诺多糖。IV组灌流马利诺聚糖+维拉帕米，V组先用姜黄素处理后再灌流马利诺聚糖，用高效液相-紫外检测法测定有效通透系数。结果我们的qRT-PCR和Western印迹结果证实，姜黄素处理的结肠癌细胞中P-糖蛋白(P-gp)的表达降低了约15倍。伊立替康增加到0.00066 cm/S，维拉帕米-复方维拉帕米组增加约11倍，其中姜黄素预处理组伊立替康增加0.00006 cm/S至0.00042 cm/S，即维拉帕米和姜黄素使P-糖蛋白抑制活性增加约7倍，发现明显增强伊立替康的癌结肠通透性。结论任何安全、合适的P-糖蛋白抑制剂联合伊立替康治疗结肠癌将提高疗效。
Study background Studies on p-glycoprotein was carried out world vide with cell lines like Caco2, MDR1-LLC-PK1 and MDR1-MDCK in-vitro, but most of the results were failed to produce similar results in-vivo. In the present study curcumin inhibitory action on p-glycoprotein increased permeability of irinotecan, so in the colon cancer it would be beneficial if curcumin used as add on therapy. Methods Intra-rectal administered of N-Nitroso N-methyl urea (2 mg/Kg) induced colon cancer. Single pass whole length of colon in-situ perfusion was carried out in rats with irinotecan to study the influence of p-glycoprotein modulators like verapamil and curcumin. The rats were divided in to 5 groups (n=6), Group I served as control perfused with 30 μg/ml of irinotecan, propronolol and phenol red. Group II was cancerous group, induced by N-methyl N-nitroso urea. Group III was perfused with irinotican in cancerous rats. Group IV, perfused with irinotican in presence of verapamil and group V was pre-treated with curcumin and then perfused with irinotican and was estimated by HPLC-UV to effective permeability coefficient. Results Our qRT-PCR and Western blot results confirmed that about 15-fold decreases in the expression of p-glycoprotein (P-gp) in curcumin treated colon cancer cells. Irinotecan was increased to 0.00066 cm/s and about 11-fold increase in verapamil-coperfused group, where curcumin pre-treated group irinotecan was increases 0.00006 cm/s to 0.00042 cm/s that is about 7-fold increase p-glycoprotein inhibitory activity by verapamil and curcumin found to be significantly enhanced the cancerous colon permeability of irinotecan. Conclusions Any safe suitable p-glycoprotein inhibitors along with irinotecan will enhance the therapeutic benefit in the treatment of the colon cancer.