Abstract
Inflammatory response plays an important role not only in the normal physiology but also in pathologies such as cancers. The Morita-Baylis-Hillman adducts (MBHA) are a novel group of synthetic molecules that have demonstrated many biological activities against some parasitic cells such as Plasmodium falciparum, Leishmania amazonensis, and Leishmania chagasi, and antimitotic activity against sea urchin embryonic cells was also related. However, little is known about the mechanisms induced by MBHA in inflammatory process and its relation with anticancer activity. The present work investigated the cytotoxicity of three MBHA derivatives (A2CN, A3CN, and A4CN), on human colorectal adenocarcinoma, HT-29 cells, and their anti-inflammatory activities were examined in lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells, being these derivatives potentially cytotoxic to HT-29 cells. Coincubation with A2CN, A3CN, or A4CN and LPS in RAW264.7 cells inhibited NO production, as well as the production of reactive oxygen species (ROS) was also repressed. The mRNA expressions of IL-1β and IL-6 were significantly downregulated by such MBHA compounds in RAW264.7 cells, but only A2CN was able to inhibit the COX-2 gene expression. We also showed that MBHA compounds decreased almost to zero the production of IL-1β and IL-6. These findings display that such MBHA compounds exhibit anticancer and anti-inflammatory activities.
Highlights
Inflammation has been linked to cancer, but only in the last decade it has been possible to understand how inflammatory cells and other tumor stromal molecules stimulate tumor progression by creating a microenvironment that is enriched by the interleukin-1β (IL-1β) and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF) cytokines, which are protagonists of chronic inflammation associated with cancers on the liver, stomach, and colon
Using subcytotoxic concentrations of MoritaBaylis-Hillman adducts (MBHA) for HT-29 cells, we tested the anti-inflammatory activity of A2CN, A3CN, and A4CN incubated with LPS (1 μg/mL) on RAW264.7 cells
To determine the effect of MBHA on Nitric Oxide (NO) production, different concentrations of A2CN, A3CN, and A4CN (2.5 μM, 5 μM, 10 μM, and 20 μM incubated with LPS) were plated with the cells for 22 h
Summary
Inflammation has been linked to cancer, but only in the last decade it has been possible to understand how inflammatory cells and other tumor stromal molecules stimulate tumor progression by creating a microenvironment that is enriched by the interleukin-1β (IL-1β) and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF) cytokines, which are protagonists of chronic inflammation associated with cancers on the liver, stomach, and colon. Chronic inflammation acts as a regulator in tumor progression by many mechanisms, including accelerated cell proliferation, avoidance of death by apoptosis, and increase in angiogenesis and metastasis [4, 6]. Such mechanism for cancer development, in the presence of chronic inflammation, involves the continuous presence of cytokines, chemokines, ROS (reactive oxygen species), oncogenes, COX-2 (cyclooxygenase-2), 5-LOX (5-lipoxygenase), and MMPs (metalloproteinases) and activation of important transcription factors such as NF-ĸB (nuclear factor-ĸB), STAT-3 (signal transducer and activator of transcription 3), AP-1 (activator protein-1), and HIF-1α (hypoxia-inducible factor 1-alpha) [7, 8]
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