RESUMO
INTRODUCTION: The pharmacological treatment of cancer has evolved from cytotoxic to molecular targeted therapy. The median survival gains of 124 drugs approved by the FDA from 2003 to 2021 is 2.8 months. Targeted therapy is based on the somatic mutation theory, which has some paradoxes and limitations. While efforts of targeted therapy must continue, we must study newer approaches that could advance therapy and affordability for patients. AREAS COVERED: This work briefly overviews how cancer therapy has evolved from cytotoxic chemotherapy to current molecular-targeted therapy. The limitations of the one-target, one-drug approach considering cancer as a robust system and the basis for multitargeting approach with polypharmacotherapy using repurposing drugs. EXPERT OPINION: Multitargeted polypharmacotherapy for cancer with repurposed drugs should be systematically investigated in preclinical and clinical studies. Remarkably, most of these proposed drugs already have a long history in the clinical setting, and their safety is known. In principle, the risk of their simultaneous administration should not be greater than that of a first-in-human phase I study as long as the protocol is developed with strict vigilance to detect early possible side effects from their potential interactions. Research on cancer therapy should go beyond the prevailing paradigm targeted therapy.
Assuntos
Antineoplásicos , Reposicionamento de Medicamentos , Terapia de Alvo Molecular , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Animais , Taxa de Sobrevida , Polifarmacologia , Desenvolvimento de MedicamentosRESUMO
The aim to access linked tetravanadate [V4O12]4- anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4'-dimethioxy-2,2'-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4- anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cuâ¯O/Cuâ¯Cu bridges. Stability studies of water-soluble 3 and 4 by UV-Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium-copper(II) systems.
Assuntos
Antineoplásicos , Complexos de Coordenação , Humanos , Cobre/farmacologia , Cobre/química , Antineoplásicos/química , Fenantrolinas/química , Vanádio/farmacologia , DNA/química , Células MCF-7 , Ânions , Fenômenos Magnéticos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , LigantesRESUMO
ABSTRACT Smilax moranensis M.Martens & Galeotti, Smilacaceae, root is a medicinal plant used among the Chatinos in Oaxaca, Mexico, to control type 2 diabetes. The objectives of the study were to isolate the bioactive compounds from the roots of Smilax and evaluate the chronic hypoglycemic effect of the ethanol-water extract. The main compounds were isolated from the methanolic extract via conventional phytochemical methods. The dried roots of S. moranensis were extracted with methanol and chromatographed on Sephadex LH 20. Fractions were chromatographed and purified on a silica gel chromatography column. The ethanol-water extract was orally administered to hyperglycemic rats for a period of 42 days, and glucose, glycated hemoglobin (HbA1c), and triacylglycerides were measured. Moreover, very-low-density lipoprotein was calculated. During the chemical investigation, three compounds were isolated and characterized, namely, 3-O-caffeoyl-quinic acid, 5-O-caffeoyl-quinic acid and trans-resveratrol, using various spectroscopic techniques. Animal experiments confirmed that the plant extract could control both the glucose and HbA1c levels. In conclusion, this study confirms that the roots of S. moranensis have hypoglycemic properties and suggests that the isolated compounds are potentially involved in this effect.