Holland M L, Panetta J A, Hoskins J M, Bebawy M, Roufogalis B D, Allen J D, Arnold J C
Department of Pharmacology, The University of Sydney, Sydney, NSW, Australia.
Biochem Pharmacol. 2006 Apr 14;71(8):1146-54. doi: 10.1016/j.bcp.2005.12.033. Epub 2006 Feb 2.
Cannabis is the most widely used illicit drug in the world. Cannabinoids are used therapeutically by some patients as they have analgesic, anti-emetic and appetite stimulant properties which palliate adverse symptoms. Use of these agents in an oncology setting raises the question of whether they act to modulate the effectiveness of concurrently administered anti-cancer drugs. The transporter, P-glycoprotein (P-gp) confers multiple drug resistance (MDR) by effluxing a diverse array of anti-cancer agents. This study was undertaken to examine the effect of cannabinoids on P-gp. Unlike the known P-gp inhibitor, PSC833, short 1h exposure to three plant-derived cannabinoids, cannabinol (CBN), cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid receptor agonist, WIN55, 212-2 (WIN) did not inhibit the efflux of the P-gp substrate Rhodamine 123 (Rh123) in either a drug-selected human T lymphoblastoid leukaemia cell line (CEM/VLB(100)) or in a mouse fibroblast MDR1 transfected cell line (77.1). However, in CEM/VLB(100) cells, prolonged 72 h exposure to the cannabinoids, THC and CBD, decreased P-gp expression to a similar extent as the flavonoid, curcumin (turmeric). This correlated with an increase in intracellular accumulation of Rh123 and enhanced sensitivity of the cells to the cytotoxic actions of the P-gp substrate, vinblastine. Taken together, these results provide preliminary evidence that cannabinoids do not exacerbate P-gp mediated MDR. Further, plant-derived cannabinoids are moderately effective in reversing MDR in CEM/VLB(100) cells by decreasing P-gp expression.
大麻是世界上使用最广泛的非法药物。一些患者将大麻素用于治疗，因为它们具有镇痛、止吐和刺激食欲的特性，可缓解不良症状。在肿瘤学环境中使用这些药物引发了一个问题，即它们是否会影响同时使用的抗癌药物的疗效。转运蛋白P-糖蛋白（P-gp）通过排出多种抗癌药物而赋予多药耐药性（MDR）。本研究旨在研究大麻素对P-gp的影响。与已知的P-gp抑制剂PSC833不同，短时间（1小时）暴露于三种植物源性大麻素大麻酚（CBN）、大麻二酚（CBD）和Δ⁹-四氢大麻酚（THC）以及合成大麻素受体激动剂WIN55,212-2（WIN），在经过药物筛选的人T淋巴母细胞白血病细胞系（CEM/VLB₁₀₀）或小鼠成纤维细胞MDR1转染细胞系（77.1）中均未抑制P-gp底物罗丹明123（Rh123）的外排。然而，在CEM/VLB₁₀₀细胞中，长时间（72小时）暴露于大麻素THC和CBD会使P-gp表达降低，其程度与类黄酮姜黄素（姜黄）相似。这与Rh123细胞内积累增加以及细胞对P-gp底物长春碱的细胞毒性作用的敏感性增强相关。综上所述，这些结果提供了初步证据，表明大麻素不会加剧P-gp介导的多药耐药性。此外，植物源性大麻素通过降低P-gp表达，在逆转CEM/VLB₁₀₀细胞的多药耐药性方面具有一定效果。
