Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models
Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models
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DOI：
10.1158/0008-5472.can-03-4046
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发表时间：
2004-10-15
期刊：
影响因子：
11.2
通讯作者：
Margalit, R
中科院分区：
文献类型：
--
作者：
Peer, D;Dekel, Y;Margalit, R
多药耐药（MDR）是由p -糖蛋白和多药耐药相关蛋白等挤压泵驱动的，是肿瘤化疗反应不佳和失败的主要原因。耐多药;在批准用于非癌症适应症及其衍生物的药物中发现了调节剂（化学增敏剂）。然而，耐多药逆转所需剂量的毒性、副作用和溶解度差阻碍了它们的临床应用。在新设计的化学增敏剂中，有些仍然存在毒性和不良反应，而另一些则进入临床试验阶段。肿瘤和耐多药泵之间的多样性表明需要几种临床批准的耐多药调节剂。在这里，我们首次报道氟西汀（百忧解），众所周知的抗抑郁药，是一种非常有效的化学增敏剂。在体外，氟西汀在耐药细胞（分别为5个和3个品系）中增强抗癌药物（多柔比星、丝裂霉素C、长春花碱和紫杉醇）的细胞毒性（10- 100倍）。氟西汀增加耐多药细胞内的药物积累并抑制这些细胞的药物外排。在体内，氟西汀在药代动力学不变的情况下，增强了阿霉素在肿瘤内的积累（12倍）。在四种同基因和人类异种移植的耐药小鼠肿瘤模型中，氟西汀和阿霉素联合治疗在肿瘤反应和生存率方面产生了显著（P < 0.001）的改善（2- 3倍）。此外，诺西汀在远低于人体安全限度的剂量下逆转了耐多药，没有严重的剂量相关毒性、不良反应和溶解度差，这些都是其他化学增敏剂的障碍。这一低剂量范围，连同本文报道的研究结果，表明氟西汀极有可能加入可能进入临床的耐多药逆转药物武器库。
Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR ;modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, nuoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.