Exploring potential molecular targets and therapeutic efficacy of beauvericin in triple-negative breast cancer cells

• Published in: Computational biology and chemistry 2024-10, Vol.112, p.108154, Article 108154
• Main Authors: Patra, Arupam, Ghosh, Siddhartha Sankar, Saini, Gurvinder Kaur
• Format: Article
• Language: English
• Subjects: 3D spheroids; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Beauvericin; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Depsipeptides - chemistry; Depsipeptides - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase 1 - metabolism; Humans; Molecular Docking Simulation; Molecular Structure; Molecular targets; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - metabolism; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple-negative breast cancer (TNBC)
• ISSN: 1476-9271; 1476-928X; 1476-928X
• DOI: 10.1016/j.compbiolchem.2024.108154

Triple negative breast cancer (TNBC) presents a significant global health concern due to its aggressive nature, high mortality rate and limited treatment options, highlighting the urgent need for targeted therapies. Beauvericin, a bioactive fungal secondary metabolite, possess significant anticancer potential, although its molecular targets in cancer cells remain unexplored. This study has investigated possible molecular targets of beauvericin and its therapeutic insights in TNBC cells. In silico studies using molecular docking and MD simulation predicted the molecular targets of beauvericin. The identified targets included MRP-1 (ABCC1), HDAC-1, HDAC-2, LCK and SYK with average binding energy of −90.1, −44.3, −72.1, −105 and −60.8 KJ/mol, respectively, implying its multifaceted roles in reversing drug resistance, inhibiting epigenetic modulators and oncogenic tyrosine kinases. Beauvericin has significantly reduced the viability of MDA-MB-231 and MDA-MB-468 cells, with IC50 concentrations of 4.4 and 3.9 µM, while concurrently elevating the intracellular ROS by 9.0 and 7.9 folds, respectively. Subsequent reduction of mitochondrial transmembrane potential in TNBC cells, has confirmed the induction of oxidative stress, leading to apoptotic cell death, as observed by flow cytometric analyses. Beauvericin has also arrested cell cycle at G1-phase and impaired the spheroid formation and clonal expansion abilities of TNBC cells. The viability of spheroids was reduced upon beauvericin treatment, exhibiting IC50 concentrations of 10.3 and 6.2 µM in MDA-MB-468 and MDA-MB-231 cells, respectively. In conclusion, beauvericin has demonstrated promising therapeutic potential against TNBC cells through possible inhibition of MRP-1 (ABCC1), HDAC-1, HDAC-2, LCK and SYK. [Display omitted] •In silico study identified MRP1, HDAC1, HDAC2, LCK and SYK as possible molecular targets of beauvericin.•Beauvericin reduced TNBC cell viability and induced oxidative stress mediated apoptosis.•It halted cell cycle progression at G1 phase•It reduced the ability of clonal expansion and regeneration of TNBC cells.•It also reduced spheroid viability and spheroid formation ability of TNBC cells.