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首页> 外文期刊>Bioorganic and Medicinal Chemistry >Modulation of paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport?
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Modulation of paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport?

机译：类黄酮衍生物对人乳腺癌细胞中紫杉醇转运的调节。 P-gp对NBD的结合亲和力与转运调节之间是否存在相关性？

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摘要

We have investigated the effect of 13 flavonoid derivatives on [~(14)C]paclitaxel transport in two human breast cancer cell lines, the adriamycin-resistant NCI/ADR-RES and sensitive MDA-MB-435. For this study, we selected representatives of aurones, chalcones, flavones, flavonols, chromones, and isoflavones with known binding affinity toward nucleotide-binding domain (NBD2) of P-glycoprotein and for which no reported work is available regarding paclitaxel transport. Aurones CB-284, CB-285, CB-287, and ML-50 most effectively inhibited P-gp related transport in the resistant line in comparison with chalcones, flavones, flavonols, chromones, and isoflavone derivatives and accordingly increased the accumulation of [ ~(14)C]paclitaxel and decreased its efflux. Those agents efficiently modulated paclitaxel transport in P-gp highly expressing resistant human breast cancer cells and they could increase the efficiency of chemotherapy in paclitaxel-resistant tumors. In contrast, the sensitive cell line responded reversely in that CB-284, CB-285, CB-287, and ML-50 significantly inhibited accumulation of [~(14)C]paclitaxel and especially CB-287, which significantly stimulated its efflux. Some, but not all, of the data correlated with the binding of flavonoid derivatives to P-gp, and indicated that even in the P-gp highly expressing NCI/ADR-RES cells, the binding was not the only factor influencing the transport of [~(14)C]paclitaxel. Opposite effects of flavonoid derivatives on the P-gp highly expressing and MDA-MB-435 non-expressing cell lines indicate that paclitaxel is not only transported by P-gp and let us assume that Mrp2 or ABCC5 seem to be good transport-candidates in these cells. The inhibition of paclitaxel accumulation and stimulation of its efflux are potentially unfavorable for drug therapy and since they could be due to modulation of drug transporters other than P-gp, their expression in tumors is of great significance for efficient chemotherapy.
机译：我们已经研究了13种类黄酮衍生物对[〜（14）C]紫杉醇转运在两种人乳腺癌细胞系，抗阿霉素的NCI / ADR-RES和敏感的MDA-MB-435中的作用。在这项研究中，我们选择了对P-糖蛋白的核苷酸结合域（NBD2）具有已知亲和力的，代表有紫杉醇转运作用的金氧烷，查耳酮，黄酮，黄酮醇，色酮和异黄酮的代表。与查尔酮，黄酮，黄酮醇，色酮和异黄酮衍生物相比，Aurones CB-284，CB-285，CB-287和ML-50最有效地抑制了抗性系中的P-gp相关转运，从而增加了[ 〜（14）C]紫杉醇并降低其流出。这些药剂有效地调节了在高表达抗性的人乳腺癌细胞P-gp中的紫杉醇转运，并且它们可以提高对紫杉醇耐药的肿瘤的化疗效率。相反，敏感细胞系的反应相反，CB-284，CB-285，CB-287和ML-50显着抑制[〜（14）C]紫杉醇，尤其是CB-287的蓄积，从而显着刺激其流出。一些但并非全部数据与类黄酮衍生物与P-gp的结合有关，并表明即使在P-gp高表达的NCI / ADR-RES细胞中，结合也不是唯一影响黄酮转运的因素。 [〜（14）C]紫杉醇。类黄酮衍生物对P-gp高表达和MDA-MB-435非表达细胞系的相反作用表明紫杉醇不仅由P-gp转运，而且我们假定Mrp2或ABCC5似乎是P-gp的良好转运候选者。这些细胞。紫杉醇积累的抑制和其流出的刺激对于药物治疗可能是不利的，并且由于它们可能是由于除P-gp以外的药物转运蛋白的调节，因此它们在肿瘤中的表达对于有效化学疗法具有重要意义。

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