Neerati Prasad, Sudhakar Yakkanti A, Kanwar Jagat R
DMPK & Clinical Pharmacology Division, Department of Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, AP, 506009, India.
Cell signaling Laboratory, Bioscience Division, Center for Cancer and Metabolism, SRI International, Menlo PArk, CA 94025, USA.
J Cancer Sci Ther. 2013 Jul 8;5:313-319.
Studies on p-glycoprotein was carried out world vide with cell lines like Caco2, MDR1-LLC-PK1 and MDR1-MDCK , but most of the results were failed to produce similar results 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.
Intra-rectal administered of N-Nitroso N-methyl urea (2 mg/Kg) induced colon cancer. Single pass whole length of colon 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.
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.
Any safe suitable p-glycoprotein inhibitors along with irinotecan will enhance the therapeutic benefit in the treatment of the colon cancer.
世界各地利用Caco2、MDR1-LLC-PK1和MDR1-MDCK等细胞系开展了关于P-糖蛋白的研究，但大多数结果未能得出相似结论。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，因此在结肠癌治疗中，若将姜黄素用作辅助治疗可能有益。
经直肠给予N-亚硝基-N-甲基脲（2毫克/千克）诱导结肠癌。对大鼠进行伊立替康单通道全结肠灌注，以研究维拉帕米和姜黄素等P-糖蛋白调节剂的影响。将大鼠分为5组（每组n = 6），第I组作为对照组，灌注30微克/毫升的伊立替康、普萘洛尔和酚红。第II组为经N-甲基-N-亚硝基脲诱导的癌组。第III组对癌鼠灌注伊立替康。第IV组在维拉帕米存在的情况下灌注伊立替康，第V组先用姜黄素预处理，然后灌注伊立替康，并通过高效液相色谱-紫外检测法评估有效渗透系数。
我们的定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法（Western blot）结果证实，姜黄素处理的结肠癌细胞中P-糖蛋白（P-gp）表达下降约15倍。伊立替康的通透率增加到0.00066厘米/秒，在维拉帕米共灌注组增加约11倍，而姜黄素预处理组伊立替康的通透率从0.00006厘米/秒增加到0.00042厘米/秒，即增加约7倍，发现维拉帕米和姜黄素显著增强了伊立替康对癌性结肠的通透性。
任何安全合适的P-糖蛋白抑制剂与伊立替康联用都将提高结肠癌治疗的疗效。
