Induction of cellular senescence and apoptosis by anti-mycobacterial drug bedaquiline in mammalian cell lines

Abstract

Abstract Background Bedaquiline (BDQ), a first-in-class diarylquinoline compound, was approved for therapy of multidrug-resistant tuberculosis (MDR-TB) by the FDA in 2012. Previous studies have shown that the addition of BDQ to the preferred regimen resulted in faster sputum-culture conversion, but more deaths compared with the placebo group. Since the mechanism of BDQ is related to ATP synthase, and ATP synthase is closely linked to aging-related diseases, we hypothesized that BDQ may cause mitochondrial dysfunction, leading to cellular apoptosis and senescence. Methods The Cell Counting Kit-8 (CCK-8) assay is used to assess the viability of cells in the presence or absence of bedaquiline treatment. We used flow cytometry to detect Annexin V-PI and ROS levels in different groups of cells. TMRM staining is performed to examine the changes in mitochondrial membrane potential of the cells. Western blot is used to measure the expression levels of proteins associated with aging and apoptosis. The β-Galactosidase kit is used for staining to examine the proportion of senescent cells in different groups. Results In the current study, we evaluated the apoptosis and senescence induction effects of BDQ in human embryonic lung fibroblasts MRC-5 cells and rat cardiomyocytes H9C2 cells and explored the potential molecular mechanisms. The results demonstrated that BDQ reduced the cell viability in a dose- and time-dependent manner. In addition, BDQ induced cellular apoptosis and senescence, and increased Reactive Oxygen Species (ROS) level. Conclusions Our results revealed that BDQ can cause cellular apoptosis and senescence for the first time, with the aim of optimizing anti-TB drug regimens in anticipation of better outcomes.