3,3',5,5'-Tetramethoxybiphenyl-4,4'diol triggers oxidative stress, metabolic changes, and apoptosis-like process by reducing the PI3K/AKT/NF-κB pathway in the NCI-H460 lung cancer cell line - 05/01/24
, Taylon Felipe Silva a, Mariana Barbosa Detoni a, Ellen Mayara Souza Cruz a, Manoela Daiele Gonçalves b, Bruna Taciane da Silva Bortoleti a, c, Fernanda Tomiotto-Pellissier a, c, d, Amanda Cristina Machado Carloto a, Maria Beatriz Madureira a, Ana Carolina Jacob Rodrigues a, c, Jéseka Gabriela Schirmann e, Aneli M. Barbosa-Dekker e, Robert F.H. Dekker f, Ivete Conchon-Costa a, Carolina Panis g, Danielle Lazarin-Bidóia a, Milena Menegazzo Miranda-Sapla a, Mário Sérgio Mantovani h, Wander R. Pavanelli aAbstract |
Lung cancer is one of the leading causes of cancer-related deaths in men and women worldwide. Current treatments have limited efficacy, cause significant side effects, and cells can develop drug resistance. New therapeutic strategies are needed to discover alternative anticancer agents with high efficacy and low-toxicity. TMBP, a biphenyl obtained by laccase-biotransformation of 2,6-dimethoxyphenol, possesses antitumor activity against A549 adenocarcinoma cells. Without causing damage to sheep erythrocytes and mouse peritoneal macrophages of BALB/c mice. In addition to being classified as a good oral drug according to in-silico studies. This study evaluated the in-vitro cytotoxic effect of TMBP on lung-cancer cell-line NCI-H460 and reports mechanisms on immunomodulation and cell death. TMBP treatment (12.5–200 μM) inhibited cell proliferation at 24, 48, and 72 h. After 24-h treatment, TMBP at IC50 (154 μM) induced various morphological and ultrastructural changes in NCI-H460, reduced migration and immunofluorescence staining of N-cadherin and β-catenin, induced increased reactive oxygen species and nitric oxide with reduced superoxide radical-anion, increased superoxide dismutase activity and reduced glutathione reductase. Treatment also caused metabolic stress, reduced glucose-uptake, intracellular lactate dehydrogenase and lactate levels, mitochondrial depolarization, increased lipid droplets, and autophagic vacuoles. TMBP induced cell-cycle arrest in the G2/M phase, death by apoptosis, increased caspase-3/7, and reduced STAT-3 immunofluorescence staining. The anticancer effect was accompanied by decreasing PI3K, AKT, ARG-1, and NF-κB levels, and increasing iNOS. These results suggest its potential as a candidate for use in future lung anticancer drug design studies.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Schematic model of the lung anticancer effect of TMBP on the NCI-H460 large cell carcinoma cell line. Caption: TMBP, 3,3',5,5'-Tetramethoxybiphenyl-4,4'-Diol; ROS, Reactive oxygen species; NO, Nitric oxide; O2.-, Superoxide anion radical; SOD, Superoxide dismutase; GSH, Reduced glutathione; Glc, Glucose; LDH, Lactate dehydrogenase; LD, Lipid droplets; LD, Lipid droplets; AV, Autophagic vacuoles; iNOS, Induzivel nitric oxide synthase; ARG-1, Arginase-1; PI3K, phosphatidylinositol-3-kinase; AKT, Protein kinase B, pAKT, Phosphoprotein kinase B; NF-κB, Nuclear factor kappa B; STAT-3, signal transducer and activator of transcription 3; ONOO-, Peroxynitrite anion;
Schematic model of the lung anticancer effect of TMBP on the NCI-H460 large cell carcinoma cell line. Caption: TMBP, 3,3',5,5'-Tetramethoxybiphenyl-4,4'-Diol; ROS, Reactive oxygen species; NO, Nitric oxide; O2.-, Superoxide anion radical; SOD, Superoxide dismutase; GSH, Reduced glutathione; Glc, Glucose; LDH, Lactate dehydrogenase; LD, Lipid droplets; LD, Lipid droplets; AV, Autophagic vacuoles; iNOS, Induzivel nitric oxide synthase; ARG-1, Arginase-1; PI3K, phosphatidylinositol-3-kinase; AKT, Protein kinase B, pAKT, Phosphoprotein kinase B; NF-κB, Nuclear factor kappa B; STAT-3, signal transducer and activator of transcription 3; ONOO-, Peroxynitrite anion;ga1Le texte complet de cet article est disponible en PDF.
Highlights |
• | TMBP treatment reduces cell viability and alters morphology in NCI-H460. |
• | The treatment reduces migratory capacity and N-cadherin and β-catenin proteins. |
• | TMBP treatment promotes oxidative and metabolic stress on lung cancer cell-line. |
• | TMBP induces the G2/M arrest phase, cell death, and reduces STAT-3 in NCI-H460. |
• | The treatment act in NCI-H460 decreases PI3K/AKT/ARG-1/NF-κB and increases iNOS. |
Abbreviations : LC, NSCLC, SCLC, TMBP, 2,6-DMP, ROS, DMSO, SEM, TEM, H2DCFDA, MTT, PBS, SBF, Glc, TMRE, H2O2, CCCP, NAC, NO, L-NAME, O2•-, SOD, GSH, LDH, Δψm, LD, NR, MDC, CPT, ELISA, iNOS, ARG-1, PI3K, AKT, pAKT, NF-κB, pNF-κB, Nrf2, KOH, Z-DEVD-AMC substrate, Ac-DEVD-CHO inhibitor, RIPA, EDTA, TME, STAT-3, EMT, OH•-, OXPHOS, CAT, PRDXs, GPXs, ONOO-, RNS
Keywords : Treatment, Cancer, Cell Death, Redox Disruption
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Vol 170
Article 115979- janvier 2024 Retour au numéro
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