Background: Breast cancer is a heterogenic disease that comprises 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 MDAMB-
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 the 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.
Conclusions: Our study offer 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.