Kang Youra, Park Min A, Heo Se-Woong, Park Su-Young, Kang Keon Wook, Park Pil-Hoon, Kim Jung-Ae
College of Pharmacy, Yeungnam University, Gyeongsang 712-749, South Korea.
Biochim Biophys Acta. 2013 Mar;1830(3):2638-48. doi: 10.1016/j.bbagen.2012.12.005.
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.
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.
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 DR5 expression. The xanthohumol-induced changes of these resistance-related molecules in MCF-7/ADR cells were synergistically increased by gamma-ray treatment.
Xanthohumol restored sensitivity of MCF-7/ADR cells to doxorubicin and radiation therapies.
Our results suggest that xanthohumol may be a potent chemo- and radio-sensitizer, and its actions are mediated through STAT3 and EGFR inhibition.
化疗药物耐药性仍是癌症治疗中的一个临床障碍。耐药癌细胞通常对电离辐射表现出交叉耐药性，这对患者具有毁灭性后果。随着对分子机制的深入了解，将有可能制定策略来克服这种交叉耐药性并提高治疗敏感性。
研究了包括黄腐酚（啤酒花中的主要黄酮类化合物）在内的天然和合成黄酮类化合物对人乳腺癌MCF-7细胞和阿霉素耐药MCF-7（MCF-7/ADR）细胞的放射增敏活性。通过基于四氮唑的比色法和流式细胞术分析化疗增敏或放射增敏作用。进行蛋白质免疫印迹分析、共聚焦显微镜检查、siRNA转染基因沉默和荧光素酶报告基因测定以检测信号分子激活情况。
在测试的黄酮类化合物中，用黄腐酚预处理细胞可通过诱导细胞凋亡使MCF-7/ADR细胞对放射治疗显著增敏。在MCF-7/ADR细胞中，单独用黄腐酚或与γ射线联合处理可显著降低抗凋亡蛋白水平。黄腐酚处理可抑制MCF-7/ADR细胞中多药耐药蛋白1（MDR1）、表皮生长因子受体（EGFR）和信号转导子及转录激活子3（STAT3）的表达水平。此外，黄腐酚处理可增加死亡受体（DR）-4和DR5的表达。γ射线处理可协同增强黄腐酚诱导的MCF-7/ADR细胞中这些耐药相关分子的变化。
黄腐酚恢复了MCF-7/ADR细胞对阿霉素和放射治疗的敏感性。
我们的结果表明，黄腐酚可能是一种有效的化疗和放射增敏剂，其作用是通过抑制STAT3和EGFR介导的。
