Focal adhesion kinase (FAK) controls several cancer aggressive potentials of cell movement and dissemination. As epithelial–mesenchymal transition (EMT) and the migratory-associated integrins, known influencers of metastasis, have been found to be linked with FAK activity, this study unraveled the potential pharmacological effect of artocarpin in targeting FAK resulting in the suppression of EMT and migratory behaviors of lung cancer cells. Treatment with artocarpin was applied at concentrations of 0–10 μM, and the results showed non-cytotoxicity in lung cancer cell lines (A549 and H460), normal lung (BEAS-2B) cells and primary metastatic lung cancer cells (ELC12, ELC16, and ELC20). We also found that artocarpin (0–10 µM) had no effect on cell viability, proliferation, and migration in BEAS-2B cells. For metastasis-related approaches, artocarpin significantly inhibited cell migration, invasion, and filopodia formation. Artocarpin also dramatically suppressed anchorage-independent growth, cancer stem cell (CSC) spheroid formation, and viability of CSC-rich spheroids. For molecular targets of artocarpin action, computational molecular docking revealed that artocarpin had the best binding affinity of −8.0 kcal/mol with FAK protein. Consistently, FAK-downstream proteins, namely active Akt (phosphorylated Akt), active mTOR (phosphorylated mTOR), and Cdc42, and EMT marker and transcription factor (N-cadherin, Vimentin, and Slug), were found to be significantly depleted in response to artocarpin treatment. Furthermore, we found the decrease of Caveolin-1 (Cav-1) accompanied by the reduction of integrin-αν and integrin-β3. Taken together, these findings support the anti-metastasis potentials of the compound to be further developed for cancer therapy.

Oxidative stress in dermal fibroblasts is strongly correlated with the aging process of the skin. The application of natural compounds that can increase the ability of dermal fibroblasts to counteract oxidative stress is a promising approach to promote skin health and beauty. Eriodictyol is a flavonoid that exerts several pharmacological actions through its antioxidant properties. However, its protective effects on dermal fibroblasts have not yet been investigated. In this study, we investigated whether eriodictyol protects human dermal fibroblasts (BJ fibroblasts) from the harmful effects of hydrogen peroxide (H2O2). Eriodictyol pretreatment significantly prevented necrotic cell death caused by H2O2 exposure. In addition, the level of 2′,7′-dichloro-dihydro-fluorescein oxidation was decreased, and that of glutathione was maintained, indicating that the beneficial effects of eriodictyol against H2O2 were closely associated with oxidative-stress attenuation. Eriodictyol mediates its antioxidant effects on dermal fibroblasts against H2O2 through (i) the direct neutralization of reactive oxygen species; (ii) the enhancement of the activities of H2O2-detoxifying enzymes, including catalase and glutathione peroxidase; and (iii) the induction of the expressions of catalase and glutathione peroxidase 1 via the activation of the Nrf2 signaling system. These results support the potential application of eriodictyol as an ingredient in skincare products for cosmeceutical and pharmaceutical purposes.

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

Four compounds, luteolin (1), 6‐γ,γ‐dimethylallylquercetin 7‐O‐β‐D‐glucopyranoside (2), 6‐γ,γ‐dimethylallylkaempferol 7‐O‐β‐D‐glucopyranoside (3), and 6‐γ,γ‐dimethylallyldihydrokaempferol 7‐O‐β‐D‐glucoside (4), were isolated for the first time from AcOEt extract of the O. integerrima flower. We then evaluated the antioxidant effects of AcOEt, butanol, and MeOH extracts and their effects on H2O2 against oxidative stress in HaCaT keratinocyte cell lines. Furthermore, 2,2‐diphenyl‐1‐picrylhydrazyl hydrate (DPPH⋅) radical scavenging activities of 1–4 were determined and their mechanisms of action on tyrosinase were predicted by in silico studies. The results revealed that the AcOEt extract and 1–3 exhibited good DPPH⋅ radical scavenging activity. Furthermore, this extract also had a significant protective effect against H2O2‐induced oxidative stress in HaCaT cells. In silico studies indicated that the activity of 1–3 may be due to tyrosinase inhibition with MM‐GBSA free binding energies of −78.9, −70.1, and −71.1 kcal mol−1, respectively, compared to 4 with an energy −56.9 kcal mol−1.

In searching for novel targeted therapeutic agents for lung cancer treatment, norcycloartocarpin from Artocarpus gomezianus was reported in this study to promisingly interacted with Akt and exerted the apoptosis induction and epithelial-to-mesenchymal transition suppression. Selective cytotoxic profile of norcycloartocarpin was evidenced with approximately 2-fold higher IC50 in normal dermal papilla cells (DPCs) compared with human lung cancer A549, H460, H23, and H292 cells. We found that norcycloartocarpin suppressed anchorage-independent growth, cell migration, invasion, filopodia formation, and decreased EMT in a dose-dependent manner at 24 h, which were correlated with reduced protein levels of N-cadherin, Vimentin, Slug, p-FAK, p-Akt, as well as Cdc42. In addition, norcycloartocarpin activated apoptosis caspase cascade associating with restoration of p53, down-regulated Bcl-2 and augmented Bax in A549 and H460 cells. Interestingly, norcycloartocarpin showed potential inhibitory role on protein kinase B (Akt) the up-stream dominant molecule controlling EMT and apoptosis. Computational molecular docking analysis further confirmed that norcycloartocarpin has the best binding affinity of -12.52 kcal/mol with Akt protein at its critical active site. As Akt has recently recognized as an attractive molecular target for therapeutic approaches, these findings support its use as a plant-derived anticancer agent in cancer therapy.