Ramachandran Cheppail, Rabi Thangaiyan, Fonseca Hugo B, Melnick Steven J, Escalon Enrique A
Research Institute, Miami Children's Hospital, Miami, FL 33155, USA.
Int J Cancer. 2003 Jul 20;105(6):784-9. doi: 10.1002/ijc.11180.
Amooranin (AMR), a plant terpenoid, isolated from Amoora rohituka, was investigated for its ability to overcome multidrug resistance in human leukemia and colon carcinoma cell lines. AMR IC(50) values of multidrug-resistant leukemia (CEM/VLB) and colon carcinoma (SW620/Ad-300) cell lines were higher (1.9- and 6-fold) than parental sensitive cell lines (CEM and SW620). AMR induced G(2)+M phase-arrest during cell cycle traverse in leukemia and colon carcinoma cell lines and the percentage of cells in G(2)+M phase increased in a dose-dependent manner. Coincubation of tumor cells with both DOX and AMR reversed DOX resistance in 104-fold DOX-resistant CEM/VLB and 111-fold DOX-resistant SW620/Ad-300 cell lines with a dose modification factor of 50.9 and 99.6, respectively. Flow cytometric assay showed that AMR causes enhanced cellular DOX accumulation in a dose-dependent manner. AMR inhibits photolabeling of P-glycoprotein (P-gp) with [(3)H]-azidopine and the blocking effect enhanced with increasing concentrations of AMR. Our results show that AMR competitively inhibits P-gp-mediated DOX efflux, suggestive of a mechanism underlying the enhanced DOX accumulation and reversal of multidrug resistance by AMR.
从印度桃花心木（Amoora rohituka）中分离出的植物萜类化合物阿莫拉宁（AMR），对其克服人类白血病和结肠癌细胞系多药耐药性的能力进行了研究。多药耐药白血病（CEM/VLB）和结肠癌细胞系（SW620/Ad-300）的AMR半数抑制浓度（IC50）值比亲本敏感细胞系（CEM和SW620）更高（分别高1.9倍和6倍）。在白血病和结肠癌细胞系的细胞周期进程中，AMR诱导G2+M期阻滞，且G2+M期细胞百分比呈剂量依赖性增加。肿瘤细胞与阿霉素（DOX）和AMR共同孵育可逆转104倍DOX耐药的CEM/VLB和111倍DOX耐药的SW620/Ad-300细胞系中的DOX耐药性，剂量修正因子分别为50.9和99.6。流式细胞术分析表明，AMR以剂量依赖性方式导致细胞内DOX积累增加。AMR抑制[3H]叠氮平对P-糖蛋白（P-gp）的光标记，且随着AMR浓度增加，阻断作用增强。我们的结果表明，AMR竞争性抑制P-gp介导的DOX外排，提示AMR增强DOX积累和逆转多药耐药性的潜在机制。
