RESUMEN
Recently we and other groups have shown that molecular iodine (I(2)) exhibits potent antiproliferative and apoptotic effects in mammary cancer models. In the human breast cancer cell line MCF-7, I(2) treatment generates iodine-containing lipids similar to 6-iodo-5-hydroxy-eicosatrienoic acid and the 6-iodolactone (6-IL) derivative of arachidonic acid (AA), and it significantly decreases cellular proliferation and induces caspase-dependent apoptosis. Several studies have shown that AA is a natural ligand of the peroxisome proliferator-activated receptors (PPARs), which are nuclear transcription factors thought to participate in regulating cancer cell proliferation. Our results show that in MCF-7 cells: (1) 6-IL binds specifically and with high affinity to PPAR proteins (EMSA assays), (2) 6-IL activates both transfected (by transactivation assays) and endogenous (by lipid accumulation) peroxisome proliferator response elements, and (3) 6-IL supplementation increases PPAR gamma and decreases PPAR alpha expression. These results implicate PPARs in a molecular mechanism by which I(2), through formation of 6-IL, inhibits the growth of human breast cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Ácidos Araquidónicos/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Yodo/farmacología , PPAR gamma/metabolismo , Animales , Antineoplásicos/uso terapéutico , Ácido Araquidónico/análisis , Ácido Araquidónico/química , Ácidos Araquidónicos/análisis , Ácidos Araquidónicos/química , Línea Celular Tumoral , Biología Computacional , Ensayo de Cambio de Movilidad Electroforética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Yodo/uso terapéutico , Radioisótopos de Yodo/química , PPAR alfa/metabolismo , PPAR gamma/química , PPAR gamma/genética , Unión Proteica , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Elementos de Respuesta , Receptores X Retinoide/química , Receptores X Retinoide/metabolismo , Coloración y EtiquetadoRESUMEN
Database screening was performed in a large database (hundreds of thousands of molecules which we optimized at the AM1 level) yielding a set of potential bioactive ligands. One new ligand was selected among the top solutions and optimized at the B3LYP/6-31G* level, yielding also NBO (Natural Bond Order) charges. A flexible docking program was used to investigate the interactions between the receptor and the new ligand. The stability as well as the main protein-ligand contacts of our proposed novel ligand as well as the crystallographic RAR ligand was investigated by molecular dynamics. The ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties as well as the parameters of the Rule of Five were investigated. The result of this work is compared with a crystallographic ligand of RAR. Our novel proposed anti-cancer ligand indicates hydrophobic interactions and strong polar interactions with the receptor.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/metabolismo , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Ligandos , Modelos Moleculares , Conformación Proteica , Teoría Cuántica , Receptores de Ácido Retinoico/química , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide/química , Receptores X Retinoide/metabolismoRESUMEN
The retinoic acid receptor (RAR) and retinoid X receptor (RXR) are members of the nuclear receptor superfamily. The ligand-binding domain contains the ligand-dependent activation function. The isotypes RARalpha,beta and gamma are distinct pharmacological targets for retinoids involved in the treatment of various cancers and skin diseases. There is thus considerable interest in synthetic retinoids with isotype selectivity and reduced side effects. In this work we have focused on the retinoid acid receptor and three of its panagonists. We have carried out density functional geometry optimizations at the B3LYP/6-31G* level, computed two types of atomic charges and also electrostatic potentials. A docking program was used to investigate the interactions between the receptor and the three ligands. A theoretically more potent inhibitor, which was obtained by modifying one of the retinoic acids investigated, is proposed.