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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。
Triple negative breast cancer is a breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her-2). Triple negative breast cancer due to high resistance and invasiveness, the traditional single chemotherapy is difficult to treat triple negative breast cancer. This study aimed to study a combination therapy of rofecoxib and daunorubicin to evaluate its activity in treating triple-negative breast cancer cells and to try to elucidate its mechanism of action. In this study, a gradient elution HPLC with simultaneous detection of two drugs was established. The mechanism of drug action on triple-negative breast cancer was evaluated using a high-content drug screening system. The cytotoxicity of Anti-cancer activity. The results showed that daunorubicin monotherapy for triple negative breast cancer was not obvious, and daunorubicin combined with rofecoxib can effectively enhance the overall anti-cancer effect, and its enhanced anti-cancer activity showed non- Cox concentration dependence. Mechanism of the results show that daunorubicin and rofecoxib in combination can be directly through the killing effect, induce cancer cell apoptosis and autophagy, thereby enhancing the anti-cancer effect. In addition, the study also confirmed that the molecular mechanism of induction of apoptosis is related to the activation of the caspase family of apoptosis enzymes and the inhibition of signaling pathways such as the Bcl-2 family of anti-apoptotic active proteins. This study shows that combination of daunorubicin and rofecoxib can effectively inhibit triple negative breast cancer cells, and initially revealed its mechanism of action. Therefore, the results of this study are expected to provide a new drug prescription and treatment strategy for the treatment of triple negative breast cancer.