The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells
The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells
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DOI：
10.1016/j.bbagen.2012.12.005
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发表时间：
2013-03-01
影响因子：
3
通讯作者：
Kim, Jung-Ae
中科院分区：
文献类型：
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作者：
Kang, Youra;Park, Min-A;Kim, Jung-Ae
背景：化疗耐药仍然是癌症治疗的临床障碍，耐药的癌细胞通常对电离辐射表现出交叉耐药，这对患者具有毁灭性的后果。随着对分子机制的更好理解，将有可能开发出克服这种交叉耐药的策略，并提高治疗敏感性。方法：研究天然类黄酮和合成类黄酮化合物黄腐酚对人乳腺癌MCF-7和抗阿霉素MCF-7 （MCF-7/ADR）细胞的放射增敏活性。采用四氮基比色法和流式细胞术分析化学增敏或放射增敏效果。Western blot分析、共聚焦显微镜、siRNA转染基因沉默和荧光素酶报告基因检测检测信号分子激活情况。结果：在所测试的类黄酮化合物中，黄腐酚预处理细胞可通过诱导细胞凋亡使MCF-7/ADR细胞对放射治疗增敏。在MCF-7/ADR细胞中，单独使用黄腐酚或伽马射线治疗可显著降低抗凋亡蛋白的水平。黄腐酚处理可抑制MCF-7/ADR细胞中多药耐药1 （MDR1）、表皮生长因子受体（EGFR）和转录信号转导因子3 （STAT3）的表达水平。此外，黄腐酚处理增加了死亡受体(DR)-4和DRS的表达。结论：黄腐酚能恢复MCF-7/ADR细胞对阿霉素和放疗的敏感性。一般意义：我们的研究结果表明黄腐酚可能是一种有效的化学和放射增敏剂，其作用是通过抑制STAT3和EGFR介导的。(C) 2012 Elsevier B.V.版权所有
Background: Chemotherapeutic drug resistance remains a clinical obstacle in cancer management Drug-resistant cancer cells usually exhibit cross-resistance to ionizing radiation, which has devastating consequences for patients. With a better understanding of the molecular mechanisms, it will be possible to develop strategies to overcome this cross-resistance and to increase therapeutic sensitivity.Methods: Natural and synthetic flavonoid compounds including xanthohumol, the principal flavonoid in hops, were investigated for its radio-sensitizing activity on human breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR) cells. Chemo-sensitizing or radio-sensitizing effect was analyzed by tetrazolium-based colorimetric assay and flow cytometry. Western blot analysis, confocal microscopy, gene silencing with siRNA transfection and luciferase reporter gene assay were performed to examine signaling molecule activation.Results: Among the tested flavonoid compounds, pretreatment of the cells with xanthohumol significantly sensitized MCF-7/ADR cells to the radiation treatment by inducing apoptosis. In MCF-7/ADR cells, treatment with xanthohumol alone or with gamma-rays significantly decreased levels of anti-apoptotic proteins. Multi-drug resistance 1 (MDR1), epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) expression levels in MCF-7/ADR cells were suppressed by xanthohumol treatment. In addition, xanthohumol treatment increased death receptor (DR)-4 and DRS expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatmentConclusions: Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies.General significance: Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition. (C) 2012 Elsevier B.V. All rights reserved.