A novel NSC small molecule inhibitor inhibits proliferation of triple‐negative breast cancer cells through metabolic reprograming

Abstract

BackgroundTreatment of patients with triple‐negative breast cancer (TNBC) has been challenging due to the absence of well‐defined molecular targets and high invasive and proliferative capacities of these cells. Current treatments against TNBC have shown minimal activity due to the high recurrence rate in the patients. There is, therefore, a pressing need for novel and efficacious therapies against TNBC. Here, we found a novel small molecule inhibitor with potent anti‐tumor activity against TNBC cells.MethodsAnti‐proliferative effects of NSC small molecule inhibitor were determined using 2D and 3D culture cell proliferation assays. Using proteomics, NGS and enrichment analysis, we globally investigated top regulatory pathways affected by this compound in TNBC cells. Subsequently, we validated the proteomics and NGS analysis data using seahorse and enzymatic assays. Finally, we showed the inhibitor anti‐tumor effects in vivo. Data were evaluated in triplicate against untreated control cells. Data were graphed and analyzed using GraphPad Prism Software 8.0 using one‐way ANOVA and the unpaired two‐tailed Student’s t‐test.ResultsIn this report, we showed that a novel NSC small molecule inhibitor reduced the proliferation of TNBC cells. Proteomic analysis confirmed a significant metabolic reprograming including suppression of glycolysis and oxidative phosphorylation after treatment. Furthermore, we found that treatment with NSC small molecule inhibitor impaired glycolysis and oxidative phosphorylation via modulating the activity of metabolic regulator enzymes.ConclusionsAltogether, our data indicate that NSC small molecule inhibitor may exhibit anti‐tumor activity in TNBC cells and provide a rationale for further investigation of the potential of NSC small molecule inhibitor as an attractive therapeutic drug for TNBC. Further in‐depth investigations are required to evaluate the exact targets and mechanism of this potent small molecule inhibitor, and its anti‐neoplasm effects on TNBC in vivo.