RESUMEN
Safer analgesic drugs remain a hard challenge because of cardiovascular and/or gastrointestinal toxicity, mainly. So, this study evaluated in vivo the antiproliferative actions of a fraction with casearins (FC) from Casearia sylvestris leaves against human colorectal carcinomas and antihyperalgesic effects on inflammatory- or opiate-based pain relief and oncologic pain in Sarcoma 180 (S180)-bearing mice. Moreover, docking investigations evaluated the binding among Casearin X and NMDA(N-methyl-D-aspartate)-type glutamate receptors. HCT-116 colorectal carcinoma-xenografted mice were treated with FC for 15 days. Antinociceptive assays included chemically induced algesia and investigated mechanisms by pharmacological blockade. Intraplantar region S180-bearing animals received a single dose of FC and were examined for mechanical allodynia and behavior alterations. AutoDock Vina determined molecular interactions among Cas X and NMDA receptor subunits. FC reduced tumor growth at i.p. (5 and 10 mg/kg) and oral (25 mg/kg/day) doses (31.12-39.27%). FC reduced abdominal pain, as confirmed by formalin and glutamate protocols, whose antinociception activity was blocked by naloxone and L-NAME (neurogenic phase) and naloxone, atropine, and flumazenil (inflammatory phase). Meanwhile, glibenclamide potentiated the FC analgesic effects. FC increased the paw withdrawal threshold without producing changes in exploratory parameters or motor coordination. Cas X generated a more stable complex with active sites of the NMDA receptor GluN2B subunits. FC is a promising antitumor agent against colorectal carcinomas, has peripheral analgesic effects by desensitizing secondary afferent neurons, and inhibits glutamate release from presynaptic neurons and/or their action on cognate receptors. These findings emphasize the use of clerodane diterpenes against cancer-related pain conditions.
RESUMEN
Matrikines are biologically active peptides generated from fragments fragmentation of extracellular matrix components (ECM) that are functionally distinct from the original full-length molecule. The active matricryptic sites can be unmasked by ECM components enzymatic degradation or multimerization, heterotypic binding, adsorption to other molecules, cell-mediated mechanical forces, exposure to reactive oxygen species, ECM denaturation, and others. Laminin α1-derived peptide (SIKVAV) is a bioactive peptide derived from laminin-111 that participates in tumor development, cell proliferation, angiogenesis in various cell types. SIKVAV has also a potential pharmaceutical activity that may be used for tissue regeneration and bioengineering in Alzheimer's disease and muscular dystrophies. In this work, we made computational analyzes of SIKVAV regarding the ADMET panel, that stands for Administration, Distribution, Metabolism, Excretion, and Toxicity. Docking analyzes using the α3ß1 and α6ß1 integrin receptors were performed to fill in the gaps in the SIKVAV's signaling pathway and coupling tests showed that SIKVAV can interact with both receptors. Moreover, there is no indication of cytotoxicity, mutagenic or carcinogenic activity, skin or oral sensitivity. Our analysis suggests that SIKVAV has a high probability of interacting with peroxisome proliferator-activated receptor-gamma (NR-PPAR-γ), which has anti-inflammatory activity. The results of bioinformatics can help understand the participation of SIKVAV in homeostasis and influence the understanding of how this peptide can act as a biological asset in the control of dystrophies, neurodegenerative diseases, and tissue engineering.Communicated by Ramaswamy H. Sarma.