Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells.
Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells.
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DOI：
10.1186/bcr2602
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Mylonas I
中科院分区：
文献类型：
--
作者：
Brüning A;Friese K;Burges A;Mylonas I
HIV蛋白酶抑制剂nelfinavir目前正在作为一种新的抗癌药物进行研究。几项研究表明，奈非那韦诱导癌细胞的细胞周期停滞、内质网应激、自噬和凋亡。在本文中，奈非那韦对人乳腺癌细胞的影响进行了检查和潜在的联合治疗进行了研究。通过分析奈非那韦和他莫昔芬对细胞活力的影响来测试它们对人乳腺癌细胞系MCF 7、T47 D、MDA-MB-453和MDA-MB-435的作用（通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化物测定），细胞凋亡（膜联蛋白结合，聚（ADP-核糖）聚合酶切割），自噬（自噬标记物轻链3B表达），内质网应激（结合蛋白和激活转录因子3表达）和氧化应激的发生（细胞内谷胱甘肽水平）。奈非那韦诱导所有四个乳腺癌细胞系的细胞凋亡测试，虽然自噬和内质网应激的程度不同的细胞系。当与他莫昔芬联合使用时，有效诱导乳腺癌细胞凋亡所需的奈非那韦浓度可从15 μg/ml降至6 μg/ml。在6 μg/ml的浓度下，他莫昔芬显著增强了对奈非那韦具有结合蛋白（BiP）上调应答的细胞系（MCF 7，T47 D）中的内质网应激反应，并增强了对奈非那韦处理具有自噬标记物轻链3B上调应答的细胞系（MDA-MB-453）中的自噬。尽管他莫昔芬在与本研究中使用的浓度（6 μg/ml）相似的浓度下能够诱导氧化应激，但我们观察到奈非那韦而不是他莫昔芬在应用后数小时内使乳腺癌细胞的细胞内谷胱甘肽水平降低高达32%，这表明氧化应激的诱导是奈非那韦诱导细胞凋亡的早期事件和额外原因。结果表明，奈非那韦可能是一种有效的抗乳腺癌药物，并可与他莫昔芬联合使用，以提高其对乳腺癌细胞的疗效。此外，他莫昔芬和奈非那韦组合的细胞毒性作用与所分析的乳腺癌细胞的雌激素受体状态无关，这表明即使在无肿瘤反应性肿瘤的患者中，这两种药物的组合也具有潜在的益处。因此，我们建议在乳腺癌患者中进行的奈非那韦临床研究应包括该药物组合，以分析该潜在治疗选择的疗效以及安全性和耐受性。
The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug. Several studies have shown that nelfinavir induces cell cycle arrest, endoplasmic reticulum stress, autophagy, and apoptosis in cancer cells. In the present article, the effect of nelfinavir on human breast cancer cells is examined and potential combination treatments are investigated. The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7, T47 D, MDA-MB-453, and MDA-MB-435 were tested by analysing their influence on cell viability (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay), apoptosis (annexin binding, poly(ADP-ribose) polymerase cleavage), autophagy (autophagy marker light chain 3B expression), endoplasmic reticulum stress (binding protein and activating transcription factor 3 expression), and the occurrence of oxidative stress (intracellular glutathione level). Nelfinavir induced apoptosis in all four breast cancer cell lines tested, although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines. The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 μg/ml to 6 μg/ml when combined with tamoxifen. At a concentration of 6 μg/ml, tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with binding protein (BiP) upregulation (MCF7, T47D), and enhanced autophagy in cell lines that responded to nelfinavir treatment with autophagy marker light chain 3B upregulation (MDA-MB-453). Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study (6 μg/ml), we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione level of breast cancer cells within hours of application by up to 32%, suggesting the induction of oxidative stress was an early event and an additional cause of the apoptosis induced by nelfinavir. The results demonstrate that nelfinavir may be an effective drug against breast cancer and could be combined with tamoxifen to enhance its efficacy against breast cancer cells. Moreover, the cytotoxic effect of a tamoxifen and nelfinavir combination was independent of the oestrogen receptor status of the analysed breast cancer cells, suggesting a potential benefit of a combination of these two drugs even in patients with no hormone-responsive tumours. We therefore recommend that clinical studies on nelfinavir with breast cancer patients should include this drug combination to analyse the therapeutic efficacy as well as the safety and tolerability of this potential treatment option.
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