中文摘要：

三阴性乳腺癌是一种雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（Her–2）均为阴性的乳腺癌。三阴性乳腺癌因具有较高的耐药性和侵袭性,传统的单药化疗难以治疗三阴性乳腺癌。本研究旨在研究一种罗非昔布与柔红霉素的联合治疗配方、评价其治疗三阴性乳腺癌细胞的活性并尝试阐述其作用机理。本研究建立了一种可同时检出两种药物的梯度洗脱高效液相紫外色谱法,并运用高内涵药物筛选系统评价了药物对于三阴性乳腺癌的作用机制,用细胞毒方法测定了其抗癌活性。结果显示,柔红霉素单药治疗对于三阴性乳腺癌作用不明显,而柔红霉素与罗非昔布联合应用可有效增强总体抗癌效应,且其增强的抗癌活性表现出罗非昔布浓度依赖性。机制研究结果表明,柔红霉素与罗非昔布联合应用可通过直接杀伤效应、诱导癌细胞凋亡和自噬,从而增强抗癌效果。此外,研究还证实了诱导凋亡效应的分子机制与激活Caspase凋亡酶家族、抑制抗凋亡活性蛋白Bcl-2家族等信号通路有关。本研究证明了柔红霉素与罗非昔布联合应用可有效抑制三阴性乳腺癌细胞,并初步揭示了其作用机制。因此,本研究结果可望为三阴性乳腺癌的治疗提供一种新的药物处方和治疗策略。

英文摘要：

Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor（ER）, progesterone receptor（PR） and human epidermal growth factor receptor-2（HER2）. A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicin and rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.