RESUMO
CONTEXT: Over expression of renin-angiotensin system (RAS) and nuclear factor-kappaB (NF-κB) has a major role in many cancers. It has been suggested that some angiotensin receptor blockers (ARBs) could reduce the proliferation of cancer cells. The role of NF-κB pathway has been documented in cell proliferation. OBJECTIVE: In this study, the role of angiotensin II and NF-κB pathway in human cervical cancer cell line (HeLa) proliferation was studied using olmesartan (as a novel Ag II antagonist) and Bay11-7082 (as NF-κB inhibitor). MATERIALS AND METHODS: HeLa cells were treated with different concentrations of olmesartan and Bay11-7082. Cell proliferation was determined after 24, 48, and 72 h by MTT assay. Synergistic activity of olmesartan with Bay11-7082 was analyzed with Compusyn software. Apoptotic cells were determined using PI staining of DNA fragmentation. RESULTS: Cell viability decreased with olmesartan and Bay11-7082 in HeLa cells by 24, 48 and 72 h. Olmesartan had synergistic activity with Bay11-7082 and combinations of olmesartan with Bay11-7082 decreased cell viability as compared with single agent treatments. Olmesartan and Bay11-7082 induced a sub-G1 peak in flow cytometry histogram of treated cells indicating that apoptotic cell death is involved in olmesartan and Bay11-7082-induced toxicity. DISCUSSION AND CONCLUSION: Results imply that olmesartan and Bay11-7082 inhibit the growth of HeLa cells as a concentration- and time-dependent mode and they have synergistic activity. Results show that RAS and NF-κB pathway blockade lead to significant cytotoxicity against tumor cell line. So, ARBs and NF-κB pathway inhibitors could be considered as good anti-cancer agents in cervix carcinoma after further studies.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Imidazóis/farmacologia , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacologia , Sulfonas/farmacologia , Tetrazóis/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Fase G1/efeitos dos fármacos , Células HeLa , Humanos , Imidazóis/efeitos adversos , Imidazóis/agonistas , Concentração Inibidora 50 , Cinética , Masculino , NF-kappa B/metabolismo , Nitrilas/efeitos adversos , Nitrilas/agonistas , Sulfonas/efeitos adversos , Sulfonas/agonistas , Tetrazóis/efeitos adversos , Tetrazóis/agonistas , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).
Assuntos
Compostos Benzidrílicos/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Sulfonas/química , Administração Oral , Animais , Compostos Benzidrílicos/agonistas , Compostos Benzidrílicos/farmacocinética , Estimulantes do Sistema Nervoso Central/agonistas , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacocinética , Agonismo Inverso de Drogas , Meia-Vida , Cinética , Modafinila , Ligação Proteica , Pirrolidinas/agonistas , Pirrolidinas/farmacocinética , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade , Sulfonas/agonistas , Sulfonas/farmacocinética , Vigília/efeitos dos fármacosRESUMO
Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and typeâ II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high-throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC50 values of 1.6 and 336â nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed inâ vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.
Assuntos
PPAR delta/agonistas , PPAR gama/agonistas , Sulfonas/uso terapêutico , Tiadiazóis/uso terapêutico , Animais , Sítios de Ligação , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Camundongos , PPAR delta/metabolismo , PPAR gama/metabolismo , Relação Estrutura-Atividade , Sulfonas/agonistas , Sulfonas/síntese química , Sulfonas/química , Tiadiazóis/agonistas , Tiadiazóis/síntese química , Tiadiazóis/químicaRESUMO
La Historia de la Terapéutica de la Lepra se divide en tres períodos: incurabilidad, monoterapia y multiterapia. Se describen las diferentes medicaciones en estos períodos y las últimas novedades así como el tratamiento de las reacciones (AU)