RESUMO
Efforts to find compounds selectively affecting cancer cells while sparing normal ones have continued to grow. Nitric oxide (NO) is critical in physiology and pathology, including cancer. It influences cellular processes like proliferation, apoptosis, and angiogenesis. The intricate interaction of NO with cancer cells offers innovative treatment possibilities, but its effects can vary by concentration and site. Ruthenium complexes capable of releasing NO upon stimulation show for this purpose. These versatile compounds can also enhance photodynamic therapy (PDT), a light-activated approach, which induces cellular damage. Ruthenium-based photosensitizers (PSs), delivering NO and producing reactive oxygen species (ROS), offer a novel strategy for improved cancer treatments. In this study, a nitro-ruthenium porphyrin conjugate: {TPyP[Ru(NO2)(bpy)2]4}(PF6)4, designated RuNO2TPyP, which releases NO upon irradiation, was investigated for its effects on lung cells (non-tumor MRC-5 and tumor A549) in 2D and 3D cell cultures. The findings suggest that this complex has potential for PDT treatment in lung cancer, as it exhibits photocytotoxicity at low concentrations without causing cytotoxicity to normal lung cells. Moreover, treatment of cells with RuNO2TPyP followed by light irradiation (4 J cm-2) can induce apoptosis, generate ROS, promote intracellular NO formation, and has anti-migratory effects. Additionally, the complex can modify tumor cell structures and induce photocytotoxicity and apoptosis in a 3D culture. These outcomes are attributed to the internalization of the complex and its subsequent activation upon light irradiation, resulting in NO release and singlet oxygen production.
Assuntos
Complexos de Coordenação , Luz , Neoplasias Pulmonares , Óxido Nítrico , Fármacos Fotossensibilizantes , Rutênio , Óxido Nítrico/metabolismo , Humanos , Rutênio/química , Rutênio/farmacologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Porfirinas/química , Porfirinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Metaloporfirinas/química , Metaloporfirinas/farmacologia , Fotoquimioterapia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacosRESUMO
Trinuclear ruthenium complexes with orthometalated phenazines of general formula [Ru3(µ3-O)(µ2-OAc)5(L)(py)2]PF6 (L = dppn, benzo[i]dipyrido[3,2-a:2',3'-c]phenazine, 1; dppz, dipyrido[3,2-a:2',3'-c]phenazine, 2; CH3-dppz, 7-methyldipyrido[3,2-a:2',3'-c]phenazine, 3; Cl-dppz, 7-chlorodipyrido[3,2-a:2',3'-c]phenazine, 4) were investigated for their cytotoxic activity toward the B16F10 murine melanoma and the L929 non-cancer cell lines and against Trypanosoma cruzi (2-4). This study also reports a multi-technique investigation into how complexes 1-4 interact with DNA and human serum albumin, HSA. At concentrations ranging from 2 to 50 µM, all the complexes reduced B16F10 murine melanoma cell viability by over 50%. Complex 4 had the highest cytotoxic effect in the series, diminishing B16F10 cell viability to 38% at 2 µM, with an overall order for anticancer activity of 4 > 2 > 3 > 1. Complexes 2-4 showed remarkable activity in inhibiting epimastigote and amastigote forms of T. cruzi. Complex 2 showed better antitrypanosomal activity than the reference drug (IC50 = 1.19 µM and IC50 = 0.25 µM for epimastigote and amastigotes forms, respectivily). Ethidium bromide (EB) displacement assays showed that DNA intercalation progressively increases with the extension of the π-conjugation of the cyclometalating ligand and the presence of substituents in the phenazinic portion (1 > 4-3 > 2), showing that complex 1 is a stronger intercalator than EB itself (Kapp > 107 M-1). Viscosity measurements followed the same trend. Cytotoxicity against cancer cells and antitrypanosomal activity follow the same order, which is different to the tendency of DNA intercalation, suggesting DNA is not the main target of these complexes. Compound 1-4 showed very high affinity with HSA (Kb â¼109 M-1). Circular dichroism results also showed that the complexes alter significantly the secondary structure of the HSA, lowering the α-helix % from 86.2 (pure protein) to less than 5% for compounds 1, 2 and 4 at 2.8 µM. These findings demonstrated the important role of phenazines for the biological activity of triruthenium compounds.