Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity.
Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity.
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DOI：
10.1016/j.bmc.2010.07.055
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发表时间：
2010-09
影响因子：
3.5
通讯作者：
Guang-min Xi;Bin Sun;Hui-Hui Jiang-Hui;F. Kong;Huiqing Yuan;H. Lou
中科院分区：
文献类型：
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作者：
Guang-min Xi;Bin Sun;Hui-Hui Jiang-Hui;F. Kong;Huiqing Yuan;H. Lou
已知P-糖蛋白(P-gp)通过作为外排泵主动将化疗药物输送出肿瘤细胞而介导多药耐药(MDR)。抑制P-gp功能可能是逆转MDR的策略之一。我们以前曾报道过马钱子素C(MC)，一种从地钱中提取的大环联苯基化合物，作为一种抗有丝分裂药物具有抗肿瘤活性。本研究旨在评价MC及其三个合成衍生物(MC1、MC2和MC3)对长春新碱耐药的KB/VCR细胞P-gp的可能调节作用。细胞毒性实验结果表明，在四种化合物中，MC对KB和KB/VCR细胞的增殖抑制作用最强，而三种MC衍生化合物在相同条件下的抗增殖活性较弱。然而，在表达P-gp的MDR细胞中，分析这些化合物在增强VCR细胞毒性方面的效力，发现MC2是一种更有效的逆转耐药性的化合物。进一步的研究表明，MC2能够减少罗丹明-123的外流，进而增加罗丹明-123和阿霉素在KB/VCR细胞中的积聚，这表明MC2通过抑制P-gp转运活性而使细胞对VCR重新增敏。此外，MC2和VCR在不抑制细胞生长的浓度下联合使用可诱导KB/VCR细胞的凋亡。这些结果表明，MC2作为一种新型有效的P-gp抑制剂，有可能作为常规化疗药物的辅助剂来逆转P-gp高表达癌细胞的多药耐药。
P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti-proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine-123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells.