背景:对化疗的耐药性是治疗三阴性乳腺癌(TNBC)患者的主要问题。临床前数据表明TNBC依赖于蛋白酶体;然而,临床观察表明,蛋白酶体抑制剂在TNBC中的疗效可能有限,这表明需要联合治疗。
方法:我们比较了硼替佐米和卡非佐米及其与纳非那韦和洛匹那韦的组合在TNBC细胞系和原代细胞中的细胞毒活性,功能性蛋白酶体抑制,和未折叠蛋白反应(UPR)的诱导。此外,我们评估了sXBP1,ABCB1和ABCG2参与药物组合的细胞毒活性.
结果:Carfilzomib,通过蛋白酶体β5+β2抑制,在TNBC中细胞毒性比硼替佐米大,抑制β5+β1蛋白酶体亚基。尼非那韦或洛匹那韦显着增强了卡非佐米的细胞毒性。卡非佐米与洛匹那韦通过在TNBC中积累过量的蛋白酶体底物蛋白诱导内质网应激和促凋亡UPR。此外,洛匹那韦通过抑制卡非佐米从表达高水平和活性的ABCB1而不是ABCG2的细胞中的输出来增加卡非佐米的胞内可用性。
结论:卡非佐米联合奈非那韦/洛匹那韦抑制蛋白酶体是TNBC的潜在治疗选择,保证进一步调查。
BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies.
METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and
lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations.
RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or
lopinavir. Carfilzomib with
lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover,
lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2.
CONCLUSIONS: Proteasome inhibition by carfilzomib combined with nelfinavir/
lopinavir represents a potential treatment option for TNBC, warranting further investigation.