Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou, China.
J Pharm Pharmacol. 2012 Jan;64(1):90-100. doi: 10.1111/j.2042-7158.2011.01378.x. Epub 2011 Nov 10.
P-glycoprotein (Pgp) overexpression in tumour cells leads to multidrug resistance (MDR) and causes failure in cancer chemotherapy. We have previously identified (±)-praeruptorin A (PA) as a potential lead compound for Pgp modulators. In this study we investigated the MDR-reversing activities of PA derivatives.
Series 7,8-pyranocoumarins with various C-3' and C-4' side chains had been semi-synthesized and their MDR-reversing activity was investigated in Pgp-overexpressing MDR tumour cell line HepG2/Dox and in a KB V1 xenograft animal model.
All 7,8-pyranocoumarins exhibited equal or higher activity in modulating Pgp. DCK (12), DMDCK (15), 16, 21, 23 and 24 at 4 µm achieved 91%∼99% decrease in IC50 value (concentration inhibiting cell growth by 50%) of anticancer agents vinblastine, doxorubicin, puromycin and paclitaxel, and were more active than others. DMDCK also remarkably enhanced the growth inhibitory effect of paclitaxel on KB V1 xenografts (P < 0.05), showing a potency required for clinical usage. Mechanistic studies suggested that these 7,8-pyranocoumarins might reverse Pgp-MDR through directly binding to substrate binding site(s) or allosteric site(s) on Pgp therefore impairing Pgp-mediated drug transport.
Results from the study suggested that 3'-O, 4'-O-aromatic acyl substituted 7,8-pyranocoumarins could serve as a new class of Pgp modulator. Acyls play an important role in maintaining and enhancing the Pgp-modulating ability of pyranocoumarins. 3,4-Dimethoxyl substituted aromatic acyls, bearing a methoxy that might interact with Pgp as hydrogen bond accepter, were shown to be the most potent for reversing MDR.
肿瘤细胞中 P-糖蛋白（Pgp）的过度表达导致多药耐药（MDR），并导致癌症化疗失败。我们之前已经确定（±）-白芷素 A（PA）是 Pgp 调节剂的潜在先导化合物。在这项研究中，我们研究了 PA 衍生物的 MDR 逆转活性。
合成了一系列具有不同 C-3'和 C-4'侧链的 7,8-吡喃香豆素，并在 Pgp 过表达的多药耐药肿瘤细胞系 HepG2/Dox 和 KB V1 异种移植动物模型中研究了它们的 MDR 逆转活性。
所有 7,8-吡喃香豆素在调节 Pgp 方面均表现出同等或更高的活性。在 4 µm 时，DCK（12）、DMDCK（15）、16、21、23 和 24 使抗癌药物长春碱、阿霉素、嘌呤霉素和紫杉醇的 IC50 值（抑制细胞生长 50%的浓度）降低了 91%∼99%，比其他药物更有效。DMDCK 还显著增强了紫杉醇对 KB V1 异种移植的生长抑制作用（P < 0.05），显示出临床应用所需的效力。机制研究表明，这些 7,8-吡喃香豆素可能通过直接结合 Pgp 的底物结合位点或变构位点来逆转 Pgp-MDR，从而削弱 Pgp 介导的药物转运。
研究结果表明，3'-O、4'-O-芳酰取代的 7,8-吡喃香豆素可以作为一类新的 Pgp 调节剂。酰基在维持和增强吡喃香豆素的 Pgp 调节能力方面发挥着重要作用。带有可能与 Pgp 相互作用作为氢键受体的甲氧基的 3,4-二甲氧基取代芳酰基显示出最强的逆转 MDR 能力。
