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.
Highlights
Breast cancer represents the most common form of cancer in women and the second most diagnosed cancer after lung cancer (11.6% of all cancer cases)
Epidermal growth factor 2 (ERBB2), formerly known as Human epidermal growth factor 2 (HER2) or HER2/neu), is a receptor tyrosine kinase that belongs to the epidermal growth factor receptor family
We report in this study that carotenoid-enriched fractions from Spondias mombin leaves demonstrate anti-HER2 positive breast carcinoma potentials via HER2 ATP kinase domain inhibition
Summary
Breast cancer represents the most common form of cancer in women and the second most diagnosed cancer after lung cancer (11.6% of all cancer cases). An average of not less than 42,000 women dies of breast cancer every year in the United States [1]. Epidermal growth factor 2 (ERBB2), formerly known as HER2 or HER2/neu), is a receptor tyrosine kinase that belongs to the epidermal growth factor receptor family. It is overexpressed in about 20% of breast cancer and is associated with a poor prognosis [4]. Plant-derived phytochemicals are known to demonstrate excellent antineoplastic properties [7, 8] These include the carotenoids; the dietary intake of carotenoids corresponds to reduced cancer risk [9]. They have therapeutic benefits in some cancers [10, 11]
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