Molecular therapy with derivatives of amino benzoic acid inhibits tumor growth and metastasis in murine models of bladder cancer through inhibition of TNFα/NFΚB and iNOS/NO pathways

Autor: Ernesto D'Orio, Lucie Charpentier, Valerie Boulanger, Julie Girouard, Jovane Hamelin-Morrissette, Denise Belgorosky, Robert Perron, Djamel Ramla, Gervais Bérubé, Céline Van Themsche, Ana María Eiján, Carlos Reyes-Moreno
Rok vydání: 2019
Předmět:
0301 basic medicine
CIENCIAS MÉDICAS Y DE LA SALUD
Biotecnología relacionada con la Salud
Cell
TNFA
Anti-Inflammatory Agents
BLADDER-CANCER
Nitric Oxide Synthase Type II
Inflammation
Nitric Oxide
Biochemistry
Biotecnología de la Salud
Metastasis
03 medical and health sciences
0302 clinical medicine
In vivo
Cell Line
Tumor
Carcinoma
medicine
Animals
Humans
Aminobenzoates
Neoplasm Metastasis
Cell Proliferation
Pharmacology
Bladder cancer
Chemistry
Tumor Necrosis Factor-alpha
INOS
NF-kappa B
medicine.disease
NFKB
3. Good health
Tumor Burden
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Urinary Bladder Neoplasms
Apoptosis
030220 oncology & carcinogenesis
Cancer research
Tumor necrosis factor alpha
Female
medicine.symptom
CANCER-RELATED INFLAMMATION
Signal Transduction
Zdroj: Biochemical pharmacology. 176
ISSN: 1873-2968
Popis: Muscle-invasive bladder cancer (MIBC) is an aggressive form of urothelial bladder carcinoma (UBC) with poorer outcomes compared to the non-muscle invasive form (NMIBC). Higher recurrent rates and rapid progression after relapse in UBC is known to be linked with chronic inflammation. Here, the preclinical murine models of NMIBC (MB49) and MIBC (MB49-I) were used to assess the antitumor effects of DAB-1, an anti-inflammatory aminobenzoic acid derivative we have developed in order to target cancer-related inflammation. A subchronic toxicity study on cancer-free mice shown that DAB-1 treatment did not affect normal mouse development or normal function of vital organs. In mice bearing MB49-I tumors, whole body accumulation of the radioconjugate [ 131I]DAB-1 was higher than in control mice, the main sites of [131I]DAB-1 accumulation being the liver (34%), the intestines (21%), and the tumors (18%). In vivo molecular therapy of ectopic and orthotopic tumors indicated that treatment with DAB-1 efficiently inhibited tumor growth, metastasis formation, and mortality rate. The antitumor efficacy of DAB-1 was associated with strong decreased tumor cell proliferation and iNOS expression in tumor tissues and deactivation of macrophages from tumor-bearing mice. Mechanistic investigations revealed that DAB-1 efficiently inhibited i) TNFα/NFΚB and IL6/STAT3 signaling pathways activation; ii) TNFα-induced NO production by decreasing NFΚB transcriptional activation and functional iNOS expression; and iii) cellular proliferation with minimal or no effects on cell mortality or apoptosis. In conclusion, this study provides preclinical and biological/mechanistic data highlighting the potential of DAB-1 as a safe and efficient therapeutic agent for the treatment of patients with NMIBC and MIBC. Fil: Girouard, Julie. Université du Québec a Montreal; Canadá Fil: Belgorosky, Denise. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Hamelin Morrissette , Jovane. Université du Québec a Montreal; Canadá Fil: Boulanger, Valerie. Université du Québec a Montreal; Canadá Fil: D'Orio, Ernesto. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Ramla, Djamel. Université du Québec a Montreal; Canadá Fil: Perron, Robert. Université du Québec a Montreal; Canadá Fil: Charpentier, Lucie. Université du Québec a Montreal; Canadá Fil: Van Themsche, Celine. Université du Québec a Montreal; Canadá Fil: Eijan, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Bérubé, Gervais. Université du Québec a Montreal; Canadá Fil: Reyes Moreno, Carlos. Université du Québec a Montreal; Canadá
Databáze: OpenAIRE
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