bedaquiline and Lung-Neoplasms

Topics: A549 Cells; Administration, Inhalation; Antibiotics, Antineoplastic; Antitubercular Agents; beta-Cyclodextrins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Diarylquinolines; Drug Carriers; Drug Repositioning; Humans; Lung Neoplasms; Models, Molecular

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths globally. Treatment-related adverse effects and development of drug resistance limit the available treatment options for most patients. Therefore, newer drug candidates and drug delivery systems that have limited adverse effects with significant anti-cancer efficacy are needed. For NSCLC treatment, delivering drugs via inhalation is highly beneficial as it requires lower doses and limits systemic toxicity. Bedaquiline (BQ), an FDA-approved anti-tuberculosis drug has previously shown excellent anti-cancer efficacy. However, poor aqueous solubility limits its delivery via the lungs. In this project, we developed inhalable BQ-loaded cubosome (BQLC) nanocarriers against NSCLC. The BQLC were prepared using a solvent evaporation technique with the cubosomal nanocarriers exhibiting a particle size of 150.2 ± 5.1 nm, zeta potential of (+) 35.4 ± 2.3 mV, and encapsulation efficiency of 51.85 ± 4.83%. The solid-state characterization (DSC and XRD) confirmed drug encapsulation and in an amorphous form within the cubosomes. The BQLC nanocarriers showed excellent aerodynamic properties after nebulization (MMAD of 4.21 ± 0.53 µm and FPF > 75%). The BQLC displayed enhanced cellular internalization and cytotoxicity with a ~ 3-fold reduction in IC

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Diarylquinolines; Humans; Lung Neoplasms; Nanoparticles; Particle Size

Tumor angiogenesis plays essential roles during lung cancer progression and metastasis. Therapeutic agent that targets both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy. We demonstrate that bedaquiline, a FDA-approved antibiotic drug, effectively targets lung cancer cells and angiogenesis. Bedaquiline dose-dependently inhibits proliferation and induces apoptosis of a panel of lung cancer cell lines regardless of subtypes and molecular heterogeneity. Bedaquiline also inhibits capillary network formation of human lung tumor associated-endothelial cell (HLT-EC) on Matrigel and its multiple functions, such as spreading, proliferation and apoptosis, even in the presence of vascular endothelial growth factor (VEGF). We further demonstrate that bedaquiline acts on lung cancer cells and HLT-EC via inhibiting mitochondrial respiration and glycolysis, leading to ATP reduction and oxidative stress. Consistently, oxidative damage on DNA, protein and lipid were detected in cells exposed to bedaquiline. Importantly, the results obtained in in vitro cell culture are reproducible in in vivo xenograft lung cancer mouse model, confirming that bedaquiline suppresses lug tumor growth and angiogenesis, and increases oxidative stress. Our findings demonstrating that energy depletion is effectively against lung tumor cells and angiogenesis. Our work also provide pre-clinical evidence to repurpose antibiotic bedaquiline for lung cancer treatment.

Topics: A549 Cells; Adenosine Triphosphate; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diarylquinolines; Dose-Response Relationship, Drug; Energy Metabolism; Humans; Lung Neoplasms; Mice; Mice, SCID; Neovascularization, Pathologic; Treatment Outcome