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Carotenoid-Enriched Fractions From Spondias mombin Demonstrate HER2 ATP Kinase Domain Inhibition: Computational and In Vivo Animal Model of Breast Carcinoma Studies.

ABSTRACT: Human epidermal growth factor 2 (HER2) is overexpressed in about 20% of breast cancer and is associated with a poor prognosis. We report in this study that carotenoid-enriched fractions from Spondias mombin demonstrate HER2 ATP kinase domain inhibition. HER2 breast carcinoma was modeled in female Wistar rats and authenticated via immunohistochemical studies. Inhibition of HER2 ATP kinase domain by the carotenoid-enriched fractions was investigated by molecular docking, atomistic simulation, and the expression of HER2 mRNA in HER2-positive breast carcinoma model in female Wistar rats. The therapeutic efficacy of the treatments (carotenoid-rich fractions) was determined by biochemical, tumor volume, and histopathological analysis. Immunohistochemical analysis revealed 7,12-dimethylbenz[a]anthracene (DMBA)-induced HER2-positive breast carcinoma. Phytoconstituents of the carotenoid-enriched fractions astaxanthin, 7,7',8,8'-tetrahydro-β,β-carotene, beta-carotene-15,15'-epoxide, and lapatinib (standard drug) demonstrate inhibition of HER2 with docking scores of -3.0, -8.5, -11.5, and -10.6 kcal/mol, respectively; and during atomistic simulation, the compounds ruptured the canonical active-state K753/E770 salt-bridge interaction. The treatment similarly downregulated HER2 mRNA expression significantly at p < 0.05. It also upregulated the expression of p53 and p27 mRNAs significantly at p < 0.05 and reduced creatinine and urea concentrations in the serum at p < 0.05. The tumor volume was also significantly reduced when compared with that of the untreated group. Carotenoid-enriched fractions from S. mombin demonstrate anti-HER2 positive breast carcinoma potentials via HER2 ATP kinase domain inhibition.

SUBMITTER: Metibemu DS

PROVIDER: S-EPMC8438527 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Carotenoid-Enriched Fractions From Spondias mombin Demonstrate HER2 ATP Kinase Domain Inhibition: Computational and In Vivo Animal Model of Breast Carcinoma Studies.

Metibemu Damilohun Samuel DS Akinloye Oluseyi Adeboye OA Omotuyi Idowu Olaposi IO Okoye Jude Ogechukwu JO Popoola Mustapha Ayodele MA Akamo Adio Jamiu AJ

Frontiers in oncology 20210831

Human epidermal growth factor 2 (HER2) is overexpressed in about 20% of breast cancer and is associated with a poor prognosis. We report in this study that carotenoid-enriched fractions from Spondias mombin demonstrate HER2 ATP kinase domain inhibition. HER2 breast carcinoma was modeled in female Wistar rats and authenticated via immunohistochemical studies. Inhibition of HER2 ATP kinase domain by the carotenoid-enriched fractions was investigated by molecular docking, atomistic si ...[more]

PMID: 34532287

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Project description:This work focused on characterizing the chemical constituents and evaluating the antioxidant and antimicrobial activities of the essential oils obtained from the fruit and leaves of Spondias mombin-a flowering plant of the Anacardiaceae family. Essential oils were extracted through steam distillation and characterized by gas chromatography-mass spectrometry. For the fruit essential oil, 35 compounds were obtained, and 25 compounds were identified in the leaf essential oil. The dominant compounds present in the fruit essential oil were (E)-ethyl cinnamate (14.06%) and benzyl benzoate (12.27%). Methyl salicylate (13.05%) and heptacosane (12.69%) were the abundant compounds in the leaf essential oil. The antioxidant activity of the essential oils was evaluated via phosphomolybdenum, hydrogen peroxide scavenging, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, and thiobarbituric acid reactive substances (TBARS) assays. The total antioxidant capacity of fruit and leaf essential oils was 48.5 ± 0.7 μg/gAAE and 48.5 ± 0.7 μg/g AAE, respectively. The half maximal scavenging concentrations of the essential oils in the hydrogen peroxide; DPPH and TBARS assays ranged from 252.2 μg/mL to 2288 μg/mL. The antimicrobial activity of the essential oils was tested using broth dilution and disc diffusion assays against eight microorganisms. The essential oils exhibited broad-spectrum antimicrobial activity against the microorganisms with minimum inhibitory concentrations of 9.75-50 mg/mL. Also, the zones of inhibition of the oils ranged from 12 mm to 25 mm. The biofilm inhibitory activities of the oils were dose-dependent with BIC50 values of 42.49 ± 0.1 mg/mL and 97.34 ± 0.6 mg/mL for fruit and leaf essential oils, respectively. Molecular docking studies revealed that the antibiofilm action of the fruit and leaf essential oils could be due to inhibition of the quorum sensing protein, LasR. The results suggest a possible application of the oils as antioxidant and antimicrobial agents.

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Carotenoid-Enriched Fractions From Spondias mombin Demonstrate HER2 ATP Kinase Domain Inhibition: Computational and In Vivo Animal Model of Breast Carcinoma Studies.

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Carotenoid-Enriched Fractions From <i>Spondias mombin</i> Demonstrate HER2 ATP Kinase Domain Inhibition: Computational and <i>In Vivo</i> Animal Model of Breast Carcinoma Studies.

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