Breast cancer is the most frequently diagnosed malignancy in women globally, representing a major global health burden, with a significant subset of cases exhibiting resistance to standard therapeutic regimens. Recently, m6A RNA demethylases such as FTO have been identified as important oncogenes in breast cancer, which modify the epitranscriptome of tumor cells to favor expression of growth-promoting genes while suppressing expression of anti-apoptotic genes. In this study, we performed virtual screening of 1,000 dietary compounds targeting the FTO protein in order to discover potential therapies for breast cancer. 7-Deshydroxypyrogallin-4-carboxylic acid (DCA) was identified as the top-ranked candidate. Molecular dynamics (MD) simulations of DCA-FTO complex displayed the formation of stable hydrogen bonds for 200 ns of MD simulations. The ADMET-prediction of DCA showed high gastrointestinal tract absorption and is not expected to be Ames-toxic. The effect of DCA on the growth of MCF-7 human breast cancer cells was assessed by Sulforhodamine B (SRB) cytotoxicity assays and found to be dose- and time-dependent. The IC₅₀ values for the growth inhibition of MCF-7 breast cancer cells were found to be 90.7 µg/mL (365.4 µM) after 24 h of treatment and 40.8 µg/mL (164.4 µM) after 48 h. As a secondary exploratory analysis, lupinine was computationally evaluated against NQO1; however, its suboptimal binding stability and safety concerns preclude experimental advancement at this stage. These findings provide a preliminary mechanistic and experimental framework for DCA as a dietary FTO inhibitor in breast cancer, necessitating further validation through orthogonal target engagement assays, m6A quantification, and in vivo tumor models.
Shuaib Pasha, S. Harishkumar, Revanth Handralu Chandraiah et al.· Naunyn-Schmiedeberg's Archiv...· 0 citations
Background KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC) is currently treated with KRAS G12C covalent inhibitors, such as sotorasib, or RAS (ON) G12-selective inhibitors; however, response rates and progression-free survival remain limited, with recurrence occurring in most patients. Although mechanisms of resistance in KRAS G12C cell lines are multifarious, they have been attributed to EGFR activation and Aurora kinase A (AURKA) signaling via Ras-related nuclear protein (Ran). Ran-GTP cooperates with Exportin-1 (XPO1), which has been identified as essential in KRAS-mutant NSCLC cells. Methods KRAS G12C NSCLC cell lines, including H2030, which is resistant to sotorasib (KRAS G12C inhibitor) and selinexor (XPO1 inhibitor), were treated with sotorasib plus selinexor following pretreatment with omeprazole (a V-ATPase proton pump inhibitor) to assess effects on cell viability and protein expression. An in vivo study was also conducted using a KRAS G12C H2030 cell-derived tumor xenograft model. Results The combination of omeprazole with sotorasib and selinexor almost completely suppressed colony formation in the KRAS G12C-mutant cell lines tested (NCI-H358, NCI-H23, NCI-H2030, and NCI-H358R). While sotorasib did not influence XPO1 protein expression in any of the cell lines, the combination of selinexor, omeprazole and sotorasib completely suppressed XPO1 expression, as well as AURKA, survivin, YAP1, MRAS, and other key proteins. In the H2030 xenograft model, tumor growth was significantly inhibited by treatment with the three-drug combination of omeprazole, sotorasib, and selinexor, with no apparent toxic side-effects or weight loss observed. Conclusions XPO1 protein suppression is not achieved with sotorasib alone in KRAS G12C NSCLC cells. Notably, the combination of sotorasib, selinexor, and omeprazole abolishes the expression of XPO1, AURKA, YAP, and MRAS. The feasibility of therapy with XPO1 inhibition plus KRAS inhibitors warrants clinical exploration.
