RESUMO
External magnetic field is characterized by low toxicity and existence of magnetic properties, which contributes to an interest in the development of products from ferromagnetic nanoparticles (FNP) for antitumor therapy. Previously we synthesized a conjugate of ferromagnetic magnetite nanoparticles and viscumin (mistletoe lectin I, MLI), which exhibits the antitumor activity. Studying the pharmacological properties of this conjugate (FNP-MLI) was directed to the evaluation of FNP-MLI elimination after intratumor injection in mice. The elimination rate of FNP-MLI was much lower than that of native plant MLI. The presence of FNP-MLI was not accompanied by undesired changes in the tumor tissue. The use of a FNP-MLI conjugate allowed us to prolong the time of MLI presence in tissues without increasing the dose of exogenous lectin. These features contribute to the prolongation of an immunomodulatory effect of MLI.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Nanopartículas de Magnetita/administração & dosagem , Proteínas Inativadoras de Ribossomos Tipo 2/farmacocinética , Toxinas Biológicas/farmacocinética , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Portadores de Fármacos/farmacocinética , Feminino , Humanos , Injeções Intralesionais , Injeções Subcutâneas , Imageamento por Ressonância Magnética , Camundongos , Camundongos SCID , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Toxinas Biológicas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Viscumin (mistletoe lectin I, MLI) in concentrations of 10-11-10-7 M causes endoplasmic reticulum stress and triggers unfolded protein response, a modulator of antitumor immunity, in target cells.
Assuntos
Estresse do Retículo Endoplasmático , Proteínas Inativadoras de Ribossomos Tipo 2/farmacocinética , Toxinas Biológicas/farmacocinética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Masculino , Camundongos , Lectinas de Plantas/administração & dosagem , Lectinas de Plantas/farmacocinética , Lectinas de Plantas/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 2/administração & dosagem , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Toxinas Biológicas/administração & dosagem , Toxinas Biológicas/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
Aralin from Aralia elata is a newly identified type II ribosome- inactivating protein, which preferentially induces apoptosis in cancer cells. In this study, we identified that the aralin receptor is a 110-kDa high-density lipoprotein-binding protein (HDLBP), which functions as a HDL receptor. The sensitivities of tumor cell lines to aralin were dependent on the expression levels of the 110-kDa HDLBP and its forced expression in aralin-resistant Huh7 cells conferred aralin sensitivity. HDLBP-knockdown HeLa cells showed a significant aralin resistance in vitro and in vivo. Conversely, ectopic expression of the 150-kDa HDLBP resulted in increased aralin sensitivity in vivo, accompanying enhanced expression of the 110-kDa HDLBP. Thus, these results showed that the 110-kDa HDLBP in lipid rafts acted as an aralin receptor and that its expression levels determined aralin sensitivity, suggesting that aralin could be a promising anticancer drug for HDLBP-overexpressing tumors.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas de Ligação a RNA/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Administração Oral , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Aralia/química , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Células HeLa , Células Hep G2 , Humanos , Lipoproteínas HDL/antagonistas & inibidores , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Microdomínios da Membrana/metabolismo , Camundongos Nus , Peso Molecular , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Receptores de Lipoproteínas/antagonistas & inibidores , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 2/química , Proteínas Inativadoras de Ribossomos Tipo 2/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ribosome-inactivating proteins (RIPs) are mainly present in plants and function to inhibit protein synthesis through the removal of adenine residues from eukaryotic ribosomal RNA (rRNA). They are broadly classified into two groups: type I and type II. Type I RIPs are a diverse family of proteins comprising a single polypeptide chain, whereas type II RIPs are heterodimeric glycoproteins comprising an A-chain (functionally equivalent to a type I RIP) linked via a disulphide bond to a B chain, mediating cell entry. In this review, we describe common type I and type II RIPs, their diverse biological functions, mechanism of cell entry, stability in plasma and antigenicity. We end with a discussion of promising applications for RIPs in biomedicine.
Assuntos
Antineoplásicos/química , Antivirais/química , Proteínas Inativadoras de Ribossomos Tipo 1/química , Proteínas Inativadoras de Ribossomos Tipo 2/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antivirais/farmacocinética , Antivirais/farmacologia , Meia-Vida , Humanos , Biossíntese de Proteínas/efeitos dos fármacos , Conformação Proteica , Proteínas Inativadoras de Ribossomos Tipo 1/farmacocinética , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 2/farmacocinética , Proteínas Inativadoras de Ribossomos Tipo 2/farmacologia , Relação Estrutura-AtividadeRESUMO
Safety of aviscumine by subcutaneous route was assessed in patients with advanced cancer refractory to chemotherapy. Patients with progressive disease received escalating doses twice weekly. Treatment of the accrued 26 patients (10 colorectal cancer (CRC), 6 soft tissue sarcoma (STS), 5 melanoma (MM), 5 others) was well tolerated without substance-related grade 3 or 4 toxicities. Grade 1/2 toxicities were predominantly injection site reactions. Aviscumine lacked dose-limiting toxicity (DLT) up to a maximal dose of 10 ng/kg. An increase of interleukin-1 beta and interferon-gamma from baseline was seen in the patient's plasma between the 1st and 11th injection. Highest release of both cytokines was in the dose range of 4-5.9 ng/kg. Interferon-gamma was not detected after doses higher than 6 ng/kg. Eight patients (5 CRC, 1 MM, 1 STS, 1 RCC) had disease stabilisation for 79-250 days (median122 days) associated with an increase of interleukin (IL)-1 beta and interferon (IFN)-gamma. Aviscumine was well tolerated and appeared to possess clinical activity at a biologically active dose between 4 and 6 ng/kg.