Trilobolide-6-O-isobutyrate from Sphagneticola trilobata acts by inducing oxidative stress, metabolic changes and apoptosis-like processes by caspase 3/7 activation of human lung cancer cell lines

•TBB exhibits drug-likeness parameters and pharmacological characteristics.•TBB treatment reduces cell viability and alters morphology in A549 and NCI-H460.•The treatment reduces migratory capacity in tumor cell lines.•TBB treatment promotes oxidative and metabolic stress in A549 and NCI-H460.•TBB i...

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Published in:Phytomedicine (Stuttgart) 2024-06, Vol.128, p.155536-155536, Article 155536
Main Authors: Concato-Lopes, Virginia Marcia, Gonçalves-Lens, Manoela Daiele, Tomiotto-Pellissier, Fernanda, Detoni, Mariana Barbosa, Cruz, Ellen Mayara Souza, Bortoleti, Bruna Taciane da Silva, Carloto, Amanda Cristina Machado, Rodrigues, Ana Carolina Jacob, Silva, Taylon Felipe, Siqueira, Elaine da Silva, de Matos, Ricardo Luís Nascimento, Alves Cardoso, Ian Lucas, Conchon-Costa, Ivete, Lazarin-Bidóia, Danielle, Arakawa, Nilton Syogo, Dekker, Robert F.H., Mantovani, Mário Sérgio, Pavanelli, Wander Rogério
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Language:English
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Summary:•TBB exhibits drug-likeness parameters and pharmacological characteristics.•TBB treatment reduces cell viability and alters morphology in A549 and NCI-H460.•The treatment reduces migratory capacity in tumor cell lines.•TBB treatment promotes oxidative and metabolic stress in A549 and NCI-H460.•TBB induces cell death through caspase activation in A549 and NCI-H460. Lung cancer, a chronic and heterogeneous disease, is the leading cause of cancer-related death on a global scale. Presently, despite a variety of available treatments, their effectiveness is limited, often resulting in considerable toxicity and adverse effects. Additionally, the development of chemoresistance in cancer cells poses a challenge. Trilobolide-6-O-isobutyrate (TBB), a natural sesquiterpene lactone extracted from Sphagneticola trilobata, has exhibited antitumor effects. Its pharmacological properties in NSCLC lung cancer, however, have not been explored. This study evaluated the impact of TBB on the A549 and NCI-H460 tumor cell lines in vitro, examining its antiproliferative properties and initial mechanisms of cell death. TBB, obtained at 98 % purity from S. trilobata leaves, was characterized using chromatographic techniques. Subsequently, its impact on inhibiting tumor cell proliferation in vitro, TBB-induced cytotoxicity in LLC-MK2, THP-1, AMJ2-C11 cells, as well as its effects on sheep erythrocytes, and the underlying mechanisms of cell death, were assessed. In silico predictions have shown promising drug-likeness potential for TBB, indicating high oral bioavailability and intestinal absorption. Treatment of A549 and NCI-H460 human tumor cells with TBB demonstrated a direct impact, inducing significant morphological and structural alterations. TBB also reduced migratory capacity without causing toxicity at lower concentrations to LLC-MK2, THP-1 and AMJ2-C11 cell lines. This antiproliferative effect correlated with elevated oxidative stress, characterized by increased levels of ROS, superoxide anion radicals and NO, accompanied by a decrease in antioxidant markers: SOD and GSH. TBB-stress-induced led to changes in cell metabolism, fostering the accumulation of lipid droplets and autophagic vacuoles. Stress also resulted in compromised mitochondrial integrity, a crucial aspect of cellular function. Additionally, TBB prompted apoptosis-like cell death through activation of caspase 3/7 stressors. These findings underscore the potential of TBB as a promising candidate for future studie
ISSN:0944-7113
1618-095X
DOI:10.1016/j.phymed.2024.155536