RESUMO
CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.
Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/administração & dosagem , NF-kappa B/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Peptídeos Penetradores de Células/efeitos adversos , Peptídeos Penetradores de Células/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/patologia , Projetos de Pesquisa , Resultado do TratamentoRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a regulatory neuropeptide that belongs to the secretin/glucagon superfamily, of which some members have shown antimicrobial activities. Contrasting to mammals, published studies on the action of PACAP in non-mammalian vertebrate immune system remain scarce. Some of our recent studies added this peptide to the growing list of mediators that allow cross-talk between the nervous, endocrine and immune systems in teleost fish. Regulation of PACAP and expression of its receptor genes has been demonstrated during an immune response mounted against acute bacterial infection in fish, though the direct effect of PACAP against fish pathogenic bacteria has never been addressed. Current work provides evidence of antimicrobial activity of Clarias gariepinus PACAP against a wide spectrum of Gram-negative and Gram-positive bacteria and fungi of interest for human medicine and aquaculture, in which computational prediction studies supported the putative PACAP therapeutic activity. Results also indicated that catfish PACAP not only exhibits inhibitory effects on pathogen growth, but also affects the proliferation of human non-small cell lung cancer cell line H460 in a dose-dependent manner. The observed cytotoxic activity of catfish PACAP against human tumor cells and pathogenic microorganisms, but not healthy fish and mammalian erythrocytes support a potential physiological role of this neuropeptide in selective microbial and cancer cell killing. All together, our findings extend the mechanisms by which PACAP could contribute to immune responses, and open up new avenues for future therapeutic application of this bioactive neuropeptide.
Assuntos
Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Peixes-Gato/imunologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Aeromonas hydrophila/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Bactérias/patogenicidade , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Peixes-Gato/microbiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Eritrócitos/efeitos dos fármacos , Hemólise , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Accumulation of the COMMD1 protein as a druggable pharmacology event to target cancer cells has not been evaluated so far in cancer animal models. We have previously demonstrated that a second-generation peptide, with cell-penetrating capacity, termed CIGB-552, was able to induce apoptosis mediated by stabilization of COMMD1. Here, we explore the antitumor effect by subcutaneous administration of CIGB-552 in a therapeutic schedule. Outstandingly, a significant delay of tumor growth was observed at 0.2 and 0.7 mg/kg (p < 0.01) or 1.4 mg/kg (p < 0.001) after CIGB-552 administration in both syngeneic murine tumors and patient-derived xenograft models. Furthermore, we evidenced that (131)I-CIGB-552 peptide was actually accumulated in the tumors after administration by subcutaneous route. A typical serine-proteases degradation pattern for CIGB-552 in BALB/c mice serum was identified. Further, biological characterization of the main metabolites of the peptide CIGB-552 suggests that the cell-penetrating capacity plays an important role in the cytotoxic activity. This report is the first in describing the antitumor effect induced by systemic administration of a peptide that targets COMMD1 for stabilization. Moreover, our data reinforce the perspectives of CIGB-552 for cancer targeted therapy.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/farmacocinética , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Artrópodes/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Feminino , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Neoplasias Experimentais/patologia , Estabilidade Proteica/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
CIGB-552 is a cell-penetrating peptide that exerts in vitro and in vivo antitumor effect on cancer cells. In the present work, the mechanism involved in such anticancer activity was studied using chemical proteomics and expression-based proteomics in culture cancer cell lines. CIGB-552 interacts with at least 55 proteins, as determined by chemical proteomics. A temporal differential proteomics based on iTRAQ quantification method was performed to identify CIGB-552 modulated proteins. The proteomic profile includes 72 differentially expressed proteins in response to CIGB-552 treatment. Proteins related to cell proliferation and apoptosis were identified by both approaches. In line with previous findings, proteomic data revealed that CIGB-552 triggers the inhibition of NF-κB signaling pathway. Furthermore, proteins related to cell invasion were differentially modulated by CIGB-552 treatment suggesting new potentialities of CIGB-552 as anticancer agent. Overall, the current study contributes to a better understanding of the antitumor action mechanism of CIGB-552.