Background: Breast cancer is a heterogenic disease that comprises of various morphologies with intrinsic subtypes and is principally responsible for casualties among female cancer patients. Triple-negative breast cancer (TNBC) is the most aggressive subtype with a high probability of relapsing, hence successful treatment can be quite challenging. The pathogenesis of TNBC remains ambiguous and the identification of dependable biomarkers for its early diagnosis is crucial to design a strategy for therapeutic armamentarium.

Objective: To clarify the folate-dependent mechanism of action causing cell death and to unravel the potential biomarkers of TNBC to defeat this consequential public health burden.

Methods: The MTT assay and the morphological examination via microscopy were carried out to examine the viability of the cells upon the administration of the blank folate-conjugated cyclodextrin nanoparticles. An untargeted metabolomic approach using Q-TOF LC/MS was performed. Multivariate analysis of the metabolomic profile was applied to the MDA-MB-231 cell line with the aim of comparing the untreated cells with the folate-conjugated cyclodextrin nanoparticles applied cells to detect possible biomarkers.

Results: The spectrophotometric and microscopic analyses revealed that MDA-MB-231 cells underwent early apoptosis following the incubation with the folate-conjugated nanoparticles for 24 h of administration. Moreover, metabolomics profiling pointed out that hexose metabolism was significantly altered. Data mining procedures showed that glycolysis, mannose, fructose, and galactose were the most affected pathways in TNBC upon blank folate-conjugated cyclodextrin nanoparticle administration and this effect was determined to be cell-specific. A perturbed hexose pathway may be the explanation of selective cell death and decelerated cell growth seen in TNBC cells.

Conclusion: Our study offers a new understanding of the underlying mechanisms of TNBC since we hereby provide evidence that hexose is one of the main driving forces for the metabolic mechanism over TNBC cells. This alternative mechanistic approach may markedly increase the effect of chemotherapy on TNBC.

背景：乳腺癌是一种异质性疾病，由具有内在亚型的各种形态组成，是女性癌症患者死亡的主要原因。三阴性乳腺癌 (TNBC) 是最具侵袭性的亚型，复发概率高，因此成功治疗可能非常具有挑战性。TNBC 的发病机制仍然不明确，并且为其早期诊断确定可靠的生物标志物对于设计治疗设备策略至关重要。

目的：阐明导致细胞死亡的叶酸依赖性作用机制，并揭示 TNBC 的潜在生物标志物，以克服这一随之而来的公共卫生负担。

方法：进行MTT测定和显微镜形态学检查以检查施用空白叶酸缀合的环糊精纳米颗粒后细胞的活力。使用 Q-TOF LC/MS 执行非靶向代谢组学方法。对 MDA-MB-231 细胞系应用代谢组学特征的多变量分析，目的是将未处理的细胞与应用叶酸缀合的环糊精纳米颗粒的细胞进行比较，以检测可能的生物标志物。

结果：分光光度法和显微镜分析表明，MDA-MB-231 细胞在与叶酸缀合的纳米颗粒孵育 24 小时后经历了早期凋亡。此外，代谢组学分析指出己糖代谢显着改变。数据挖掘程序表明，糖酵解、甘露糖、果糖和半乳糖是在空白叶酸偶联环糊精纳米颗粒给药后 TNBC 中受影响最大的途径，并且这种影响被确定为细胞特异性的。受扰的己糖途径可能是 TNBC 细胞中出现的选择性细胞死亡和细胞生长减速的解释。

结论：我们的研究提供了对 TNBC 潜在机制的新理解，因为我们在此提供证据表明己糖是 TNBC 细胞代谢机制的主要驱动力之一。这种替代的机制方法可能会显着增加化疗对 TNBC 的影响。