Novel 9-Benzylaminoacridine Derivatives as Dual Inhibitors of Phosphodiesterase 5 and Topoisomerase II for the Treatment of Colon Cancer.

It has been shown that phosphodiesterase 5 (PDE5) inhibitors have anticancer effects in a variety of malignancies in both in vivo and in vitro experiments. The role of cGMP elevation in colorectal carcinoma (CRC) has been extensively studied. Additionally, DNA topoisomerase II (Topo II) inhibition is a well-established mechanism of action that mediates the effects of several approved anticancer drugs such as doxorubicin and mitoxantrone. Herein, we present 9-benzylaminoacridine derivatives as dual inhibitors of the PDE5 and Topo II enzymes. We synthesized 31 derivatives and evaluated them against PDE5, whereby 22 compounds showed micromolar or sub-micromolar inhibition. The anticancer activity of the compounds was evaluated with the NCI 60-cell line testing. Moreover, the effects of the compounds on HCT-116 colorectal carcinoma (CRC) were extensively studied, and potent compounds against HCT-116 cells were studied for their effects on Topo II, cell cycle progression, and apoptosis. In addition to exhibiting significant growth inhibition against HCT116 cells, compounds 11, 12, and 28 also exhibited the most superior Topo II inhibitory activity and low micromolar PDE5 inhibition and affected cell cycle progression. Knowing that compounds that combat cancer through multiple mechanisms are among the best candidates for effective therapy, we believe that the current class of compounds merits further optimization and investigation to unleash their full therapeutic potential.

Apremilast ameliorates acute respiratory distress syndrome by inhibiting neutrophil-induced oxidative stress.

BACKGROUND: The pathogenesis of acute respiratory distress syndrome (ARDS) is attributed to the dysregulation of oxidative stress and neutrophil recruitment. We aimed to investigate the anti-inflammatory effects of apremilast on human neutrophils and assess its efficacy for treating ARDS. METHODS: We analysed superoxide anion generation, integrin expression, and adhesion in activated human neutrophils using spectrophotometry, flow cytometry, and immunofluorescence microscopy. Phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was determined using immunoblotting. A murine lipopolysaccharide (LPS)-induced ARDS model was used to evaluate the therapeutic effects of apremilast. RESULTS: Apremilast significantly decreased superoxide anion production, reactive oxygen species (ROS) generation, cluster of differentiation (CD)11 b expression, and neutrophil adhesion in formyl-l-methionyl-l-leucyl-l-phenylalanine activated human neutrophils. Apremilast elevated cyclic 3',5'-adenosine monophosphate (cAMP) and protein kinase A (PKA) activity in activated neutrophils. It reduced cellular cAMP-specific phosphodiesterase (PDE) activity and selectively inhibited enzymatic PDE4 activity. The activated cAMP/PKA pathway suppressed the phosphorylation of ERK and JNK as well as Ca2+ mobilization in activated neutrophils. All inhibitory effects of apremilast on activated neutrophils were reversed by a PKA inhibitor. In vivo examinations indicated that apremilast alleviated lung neutrophil infiltration, myeloperoxidase (MPO) activity, pulmonary oedema, and alveolar damage in LPS-induced ARDS. CONCLUSION: Apremilast inhibits inflammatory responses after neutrophil activation via cAMP/PKA-dependent inhibition of ERK and JNK activation. Our study revealed apremilast suppresses oxidative stress and chemotaxis by selectively inhibiting PDE4 in neutrophils and thus protects against endotoxin-induced ARDS in mice. Apremilast can be used as an alternative off-label drug in treating acute lung damage.

Resveratrol suppresses neutrophil activation via inhibition of Src family kinases to attenuate lung injury.

The natural stilbenoid, Resveratrol (RSV; 3,5,4'-trihydroxystilbene) has been shown to have beneficial effects on inflammatory diseases as well as cancer, neurodegenerative diseases, and cardiovascular disorders. The underlying mechanism by which RSV affects neutrophil activation has yet to be fully elucidated. In this study, we tested the hypothesis that RSV modulates the inflammatory activities of formyl-Met-Leu-Phe-stimulated human neutrophils. We employed a well-established isolated-neutrophil model to investigate the effects of RSV on neutrophil functions and the underlying mechanism of signaling transduction. The lipopolysaccharide-induced ALI murine model was employed to evaluate the therapeutic effects of RSV. Experiment results demonstrate that RSV reduces respiratory burst, degranulation, integrin expression, and cell adhesion in activated neutrophils in dose-dependent manners. RSV inhibited phosphorylation of Src family kinases (SFKs) and reduced their enzymatic activities. Moreover, RSV and a selective inhibitor of SFKs (PP2) reduced the phosphorylation of Bruton's tyrosine kinase and Vav. There results indicated that the inhibitory effects of RSV are mediated through the inhibition of the SFKs-Btk-Vav pathway. This study also revealed that RSV attenuates endotoxin-induced lung injury. We surmise that the therapeutic effects of RSV on ALI may derive from its anti-neutrophilic inflammation function and free radical-scavenging effects.