RESUMEN
The ß2adrenergic receptor (ß2AR, encoded by the ADRB2 gene) is a member of the Gproteincoupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that ßblockers (ßAR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 singlenucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of ß2AR, which may alter the ßblocker drug response. The aim of the present study was to investigate the effect of ßblockers on triplenegative breast cancer cells and determine whether ADRB2 SNPs affect the response to ßblocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDAMB231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellularsignalregulated kinase (ERK)1/2 and the expression levels of cyclooxygenase 2 (COX2) were significantly decreased following ßblocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wildtype group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDAMB231 cells by downregulating the ERK/COX2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Receptores Adrenérgicos beta 2/genética , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Fosforilación/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Propanolaminas/farmacología , Propanolaminas/uso terapéutico , Propranolol/farmacología , Propranolol/uso terapéutico , Receptores Adrenérgicos beta 2/metabolismo , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
AIM: The clinical efficacy of valproic acid (VPA) varies greatly among epileptic patients. To find the potential genetic factors related to VPA responses, the pharmacogenetics study was conducted. METHODS: Two hundred and one Chinese Han epileptic patients who were treated by VPA for at least 1 year were recruited. Up to 24 SNPs in 11 candidate genes that correlate with the metabolism, transport or target of VPA were genotyped. RESULTS: Three SNPs, rs1731017 (ABAT), rs2304016 (SCN2A) and rs1054899 (ALDH5A1) were found associated with VPA responses with the p-values of 0.003, 0.007 and 0.048, respectively. Further interaction analysis showed that the interaction between rs17183814 (ABAT) and rs1641022 (SCN2A) was also correlated with the response of VPA (p = 0.006). CONCLUSION: This study found three SNPs and one interaction among ABAT, SCN2A and ALDH5A1 were significantly associated with VPA response, which indicated that these genes may play important roles in the pharmacological mechanism of VPA.
Asunto(s)
4-Aminobutirato Transaminasa/genética , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Canal de Sodio Activado por Voltaje NAV1.2/genética , Polimorfismo de Nucleótido Simple , Succionato-Semialdehído Deshidrogenasa/genética , Ácido Valproico/uso terapéutico , Adolescente , Niño , Preescolar , Epilepsia/genética , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
ß-ARs are extensively spread in different tissues of our body, which could be activated by neurotransmitters norepinephrine and epinephrine to mediate physiological function and abnormal states including cancer. Recently, ß-AR blockers could have significant implications in cancer therapy. But the precise molecular mechanisms are far from being fully understood. Through identifying the ß-AR system signal pathways relevant to cancer, we can understand the mechanisms of ß-blockers used for cancer treatment. What's more, retrospective clinical data made ß-blockers jump out of the traditional field of cardiovascular disease and strengthened our confidence in cancer therapy. At last, genetic studies of ß-adrenergic system offered crucial genes to analyze the effects of polymorphisms on cancer susceptibility, therapy response and prognosis of cancer patients.