RESUMEN
A novel class of platinum(II) complexes of pyridine sulfide derivatives of triazine was synthesized, characterized, and investigated using the human breast cancer cell line, MDA-MB-468. S-30 was one of the most potent derivatives of its class (IC(50), 0.39 microM) eliciting the greatest biological response. S-30 induced arrest in the G1 phase and apoptosis (TUNEL assay) in a p53/p21(WAF1/CIP1)-consistent manner. Modeling and docking experiments were performed for three known targets for cisplatin, d(GpG), d(ApG), and a protein (Cu/Zn superoxide dismutase, SOD) from bovine origin. A Blast search of bovine SOD was performed to identify analogous human protein targets resulting in about 22 human proteins. A multi-sequence alignment of those targets showed >80% sequence identity and >88% similarity. One of them is SOD1 that is differentially expressed (based on global gene expression pattern) in various forms of cancer and other diseases. SOD1 controls apoptosis via p53/BAD/BAX/BCL2 in the amyotrophic lateral sclerosis (ALS) pathway and is also involved in various other KEGG's pathways. Results suggest that the S-30 is a potential cytotoxic agent.
Asunto(s)
Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Fase G1/efectos de los fármacos , Platino (Metal)/farmacología , Triazinas/síntesis química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bovinos , Línea Celular Tumoral , Simulación por Computador , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Platino (Metal)/uso terapéutico , Unión Proteica , Relación Estructura-Actividad , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Triazinas/farmacología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Epidermal growth factor (EGF) caused an increase in phosphoinositide (PI) turnover in MDA 468 cells. This EGF-stimulated effect was inhibited by the protein tyrosine kinase inhibitor lavendustin A (LA). MDA 468 cells generated an atypical PI turnover profile. Examination and quantitation of the PI metabolite profile showed that even control cells produced a metabolite which was acid-labile and which formed about 60% of the total PI metabolites. By using the technique of electrospray ionization tandem mass spectrometry, we were able to confirm the identity of this acid-labile metabolite through the specific fragmentation as compared with the standard. The precursor molecule fragmented into two distinct productions with molar masses identical to that of the standard myo-inositol 1,2-cyclic monophosphate (cInsP). Changes in the PI turnover profile could be accounted for by the alterations in myo-inositol 1,2-cyclic monophosphate generated in these cells. We thus conclude that, by some as-yet-unidentified mechanism, cyclic inositol monophosphate forms a major constituent of EGF-stimulated PI turnover in MDA 468 cells.
