Background: Multidrug resistance (MDR) in triple-negative breast cancer (TNBC) leads to treatment failure and tumor recurrence. Dysregulation of the MYC oncogene is associated with the pathogenesis of TNBC and the development of chemoresistance via overexpression of ATP-binding cassette (ABC) transporters. Therefore, in the present study, we aimed to identify molecules from a natural product origin that prevent the development of MDR in TNBC by targeting the MYC signaling. Methods: The cell viability of TNBC was evaluated using sulforhodamine assay. Protein levels were detected by western blots or enzyme-linked immunosorbent assays. Intracellular calcein and hoechst33342 accumulation assay aimed to evaluate the inhibitory ability of phytocompounds on drug-efflux functions ofABCB1andABCG2transporters. The Cancer Genome Atlas (TCGA) database was used to explore clinical genomic data. Furthermore, the zebrafish xenotransplantation model bearing Dil-labeled TNBC cells was applied to testify the in vivo effects of phyto-sesquiterpene lactones. Results: The results of the present study demonstrated that the phyto-sesquiterpene lactones exhibited an MDR prevention effect by repressing efflux activities ofABCB1andABCG2transporters. Mechanistic studies showed that phyto-sesquiterpene lactones inducted TNBC cell apoptosis and cell cycle G2/M arrested by blocking the STAT3/MYC pathway. Clinical genomic data demonstrated that the percentages of MYC amplification and mRNA were upregulated approximately two-fold higher in the TNBC patients than the non-TNBC breast cancer patients. The survival of patients with an alteration in MYC was significantly lower in TNBC as compared to other subtypes. Moreover, the results of the zebrafish xenograft model confirmed that phyto-sesquiterpene lactones exerted stronger inhibitory effects on TNBC tumor growth in vivo. Conclusions: In conclusion, these three phyto-sesquiterpene lactones were promising candidates for TNBC treatment and shed light on the prevention of developing MDR TNBC.
背景：三阴性乳腺癌（TNBC）的多药耐药性（MDR）导致治疗失败和肿瘤复发。MYC癌基因的失调与TNBC的发病机制以及通过ATP结合盒（ABC）转运蛋白过表达导致的化疗耐药性发展相关。因此，本研究旨在从天然产物中筛选出能够通过靶向MYC信号通路来预防TNBC中MDR发展的分子。方法：采用磺酰罗丹明B法评估TNBC细胞活力。通过蛋白质印迹或酶联免疫吸附试验检测蛋白水平。细胞内钙黄绿素和Hoechst33342积累实验旨在评估植物化合物对ABCB1和ABCG2转运蛋白药物外排功能的抑制能力。利用癌症基因组图谱（TCGA）数据库分析临床基因组数据。此外，应用携带Dil标记TNBC细胞的斑马鱼异种移植模型验证植物倍半萜内酯的体内效应。结果：本研究结果表明，植物倍半萜内酯通过抑制ABCB1和ABCG2转运蛋白的外排活性，展现出预防MDR的作用。机制研究表明，植物倍半萜内酯通过阻断STAT3/MYC通路，诱导TNBC细胞凋亡和细胞周期G2/M期阻滞。临床基因组数据显示，与非TNBC乳腺癌患者相比，TNBC患者中MYC基因扩增和mRNA表达上调的比例高出约两倍。与其他亚型相比，MYC发生改变的TNBC患者生存率显著降低。此外，斑马鱼异种移植模型结果证实，植物倍半萜内酯在体内对TNBC肿瘤生长具有更强的抑制作用。结论：总之，这三种植物倍半萜内酯是治疗TNBC的潜在候选药物，并为预防MDR TNBC的发展提供了新的思路。
肿瘤(癌症)患者之家