Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Planta Med. 2011 Dec;77(18):1990-5. doi: 10.1055/s-0031-1280054. Epub 2011 Jul 22.
The resistance to chemotherapeutic drugs by cancer cells is considered to be one of the major obstacles for success in the treatment of cancer. A major mechanism underlying this multidrug resistance is the overexpression of P-glycoprotein (P-gp), resulting in insufficient drug delivery to the tumor sites. A previous study has shown that stemofoline, an alkaloid isolated from Stemona burkillii, could enhance the sensitivity of chemotherapeutics in a synergistic fashion. In the present study, we have focused on the effect of stemofoline on the modulation of P-gp function in a multidrug resistant human cervical carcinoma cell line (KB-V1). The effects of stemofoline on a radiolabeled drug, [(3)H]-vinblastine, and fluorescent P-gp substrates, rhodamine 123 and calcein-AM accumulation or retention were investigated to confirm this finding. Stemofoline could increase the accumulation or retention of radiolabeled drugs or fluorescent P-gp substrates in a dose-dependent manner. For additional studies on drug-P-gp binding, P-gp ATPase activity was stimulated by stemofoline in a concentration-dependent manner. More evidence was offered that stemofoline inhibits the effect on photoaffinity labeling of P-gp with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner. These data indicate that stemofoline may interact directly with P-gp and inhibit P-gp activity, whereas stemofoline has no effect on P-gp expression. Taken together, the results exhibit that stemofoline possesses an effective MDR modulator, and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells.
癌细胞对化疗药物的耐药性被认为是癌症治疗成功的主要障碍之一。这种多药耐药性的一个主要机制是 P-糖蛋白（P-gp）的过度表达，导致药物不能充分递送到肿瘤部位。先前的研究表明，从百部科植物直立百部中分离得到的生物碱石蒜宁可以协同增强化疗药物的敏感性。在本研究中，我们专注于石蒜宁对多药耐药人宫颈癌（KB-V1）细胞系中 P-gp 功能的调节作用。研究了石蒜宁对放射性标记药物[（3）H]-长春碱和荧光 P-gp 底物罗丹明 123 和 calcein-AM 积累或保留的影响，以证实这一发现。石蒜宁可以以剂量依赖的方式增加放射性标记药物或荧光 P-gp 底物的积累或保留。为了进一步研究药物-P-gp 结合，石蒜宁以浓度依赖的方式刺激 P-gp ATP 酶活性。更多证据表明，石蒜宁以浓度依赖的方式抑制[（125）I]-碘代芳基氮唑嗪与 P-gp 的光亲和标记作用。这些数据表明，石蒜宁可能直接与 P-gp 相互作用并抑制 P-gp 活性，而石蒜宁对 P-gp 表达没有影响。总之，这些结果表明石蒜宁具有有效的 MDR 调节剂作用，可与常规化疗药物联合使用，逆转癌细胞的 MDR。
