School of Life Science, Northeast Agricultural University, Harbin, China.
Eur J Pharmacol. 2011 Jun 1;659(2-3):108-13. doi: 10.1016/j.ejphar.2011.03.023. Epub 2011 Mar 31.
Development of agents to overcome multidrug resistance (MDR) is important in cancer chemotherapy, and the overexpression of P-glycoprotein (P-gp) is one of the major mechanisms of MDR. In this paper, we evaluated the effects of two new milbemycin compounds, milbemycin β(14) and secomilbemycin D, isolated from fermentation broth of S. bingchenggensis on reversing MDR of adriamycin-resistant human breast carcinoma (MCF-7/adr) cells. We observed that the both milbemycins (5 μM) showed strong potency to increase adriamycin cytotoxicity toward MCF-7/adr cells with reversal fold (RF) of 13.5 and 10.59, respectively. In addition, the mechanisms of milbemycins on reversing P-gp-mediated MDR demonstrated that they significantly increased the accumulations of adriamycin and Rh123 via inhibiting P-gp efflux in MCF-7/adr cells. Furthermore, the results also revealed that milbemycin β(14) and secomilbemycin D could regulate down the expression of P-gp, but not affect the expression of MDR1 gene. In conclusion, our observations suggest that the two new milbemycin compounds probably represent the promising agents for reversing MDR in cancer therapy.
开发克服多药耐药性（MDR）的药物在癌症化疗中非常重要，而 P-糖蛋白（P-gp）的过度表达是 MDR 的主要机制之一。在本文中，我们评估了两种从 S. bingchenggensis 发酵液中分离得到的新型米尔贝霉素化合物米尔贝霉素β(14)和 sec omilbemycin D 对逆转阿霉素耐药人乳腺癌（MCF-7/adr）细胞 MDR 的影响。我们观察到这两种米尔贝霉素（5 μM）均能显著增强阿霉素对 MCF-7/adr 细胞的细胞毒性，逆转倍数（RF）分别为 13.5 和 10.59。此外，米尔贝霉素逆转 P-gp 介导的 MDR 的机制表明，它们通过抑制 MCF-7/adr 细胞中的 P-gp 外排，显著增加了阿霉素和 Rh123 的积累。此外，结果还表明，米尔贝霉素β(14)和 sec omilbemycin D 可以下调 P-gp 的表达，但不影响 MDR1 基因的表达。总之，我们的观察结果表明，这两种新型米尔贝霉素化合物可能代表了癌症治疗中逆转 MDR 的有前途的药物。
