The leaves of Hancornia speciosa Gomes (Apocynaceae), a medicinal species found in the Brazilian cerrado biome, are traditionally used to treat wounds and inflammatory disorders. The goal of the present study was to investigate the in vitro wound healing properties of ethanolic extract of H. speciosa leaves and its isolated compounds, using the scratch assay, and to evaluate their effects on the release of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) by lipopolysaccharide (LPS)-stimulated human acute monocytic (THP-1) cells. H. speciosa ethanolic extract significantly increased (42.8% ± 5.4 at 25 µg/mL) cell migration and proliferation of fibroblasts compared with control cells, as well as the isolated compounds bornesitol (80.8% ± 5.1) and quinic acid (69.1% ± 6.2), both assayed at 50 μM. TNF-α release by LPS-stimulated THP-1 cells was significantly reduced by the ethanolic extract (62.9% ± 8.2, i.e. 1791.1 ± 394.7 pg/mL) at 10 µg/mL, bornesitol (48.9% ± 0.9, i.e. 2461.6 ± 43.1 pg/mL) at 50 μM, and quinic acid (90.2% ± 3.4, i.e. 473.5 ± 164.4 pg/mL) and rutin (82.4% ± 5.6, i.e. 847.0 ± 271.8 pg/mL) at 10 μM. These results provided evidences to support the traditional use of H. speciosa leaves to treat wounds and inflammatory disorders.
Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumour cell lines. Both compounds showed anti-proliferative effects in all tumour cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.
Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer.
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