Umsumarng Sonthaya, Pintha Komsak, Pitchakarn Pornsiri, Sastraruji Kwankamol, Sastraruji Thanapat, Ung Alison T, Jatisatienr Araya, Pyne Stephen G, Limtrakul Pornngarm
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Chem Pharm Bull (Tokyo). 2013;61(4):399-404. doi: 10.1248/cpb.c12-00967. Epub 2013 Jan 26.
Resistance to chemotherapy in cancer patients has been correlated to the overexpression of the ATP-binding cassette (ABC) drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. We examined the multidrug resistance reversing property of stemofoline derivatives in drug-resistance human cervical carcinoma (KB-V1) and human leukemic (K562/Adr) cell lines that overexpress P-gp. Didehydrostemofoline and eleven of its derivatives were synthesized and the cytotoxicity and their effect on doxorubicin, vinblastine and paclitaxel sensitivity in drug resistant (KB-V1 and K562/Adr) and drug sensitive (KB-3-1 and K562) cell lines by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were determined. We found that three out of the twelve stemofoline derivatives including OH-A1, NH-B6 and NH-D6 showed commitment efficiency to increase sensitivity to doxorubicin, vinblastine and paclitaxel in KB-V1 cells and increase sensitivity to doxorubicin, and paclitaxel in K562/Adr cells whereas the effects have not been seen in their parental sensitive cancer cell lines (KB-3-1 and K562). These results indicate that stemofoline derivatives reversed P-gp-mediated multidrug resistance in vitro, and thus could be developed as effective chemosensitizers to treat multidrug-resistant cancers. The molecular mechanism of modulation of P-gp would be further determined.
癌症患者对化疗的耐药性与ATP结合盒（ABC）药物转运蛋白的过表达相关，其中包括P-糖蛋白（P-gp），它能将化疗药物从癌细胞中主动外排。我们检测了百部碱衍生物对过表达P-gp的耐药性人宫颈癌（KB-V1）和人白血病（K562/Adr）细胞系的多药耐药逆转特性。合成了去氢百部碱及其11种衍生物，并通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测定了它们对耐药（KB-V1和K562/Adr）和药物敏感（KB-3-1和K562）细胞系的细胞毒性及其对阿霉素、长春碱和紫杉醇敏感性的影响。我们发现，包括OH-A1、NH-B6和NH-D6在内的12种百部碱衍生物中的3种，在KB-V1细胞中表现出提高对阿霉素、长春碱和紫杉醇敏感性的作用，在K562/Adr细胞中表现出提高对阿霉素和紫杉醇敏感性的作用，而在其亲本敏感癌细胞系（KB-3-1和K562）中未观察到这些作用。这些结果表明，百部碱衍生物在体外逆转了P-gp介导的多药耐药性，因此有望开发成为治疗多药耐药癌症的有效化学增敏剂。P-gp调节的分子机制将进一步确定。
