RESUMEN
Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rationally designed combination strategies. Here, through an anticancer drug screening, we show that DNA-dependent protein kinase (DNA-PK) inhibition sensitizes cancer cells to OV M1 and improves therapeutic effects in refractory cancer models in vivo and in patient tumour samples. Infection of M1 virus triggers the transcription of interferons (IFNs) and the activation of the antiviral response, which can be abolished by pretreatment of DNA-PK inhibitor (DNA-PKI), resulting in selectively enhanced replication of OV M1 within malignancies. Furthermore, DNA-PK inhibition promotes the DNA damage response induced by M1 virus, leading to increased tumour cell apoptosis. Together, our study identifies the combination of DNA-PKI and OV M1 as a potential treatment for cancers.
Asunto(s)
Antivirales/farmacología , Daño del ADN , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Virus Oncolíticos/fisiología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Terapia Combinada , Proteína Quinasa Activada por ADN/metabolismo , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Viroterapia Oncolítica , Inhibidores de Proteínas Quinasas/farmacología , RatasRESUMEN
BACKGROUND: The effect of folic acid on cardiac myocyte apoptosis secondary to diabetes is unknown. METHODS: Diabetic rats were divided into diabetic control (DC, n = 11), low-dose (LDF, 0.4 mg/kg/day, n = 12) and high-dose (HDF, 1.2 mg/kg/day, n = 12) folic acid groups. Non-diabetic rats (n = 11) were used as the normal control (NC). RESULTS: After 11 weeks of treatment, compared with the NC group, the DC group showed a reduced blood levels of reactive oxygen species (ROS, P < 0.01). The rate of cardiac myocyte apoptosis in the diabetic control group was also greater than in the non-diabetic control group (P < 0.01). In folic acid-treated rats, the blood levels of ROS was higher than in the diabetic control group (P < 0.05). There was a dose-dependent reduction in the rate of cardiac myocyte apoptosis in the folic acid groups (P < 0.01), and this was accompanied by an increased level of anti-apoptotic protein Bcl-2 and decreased level of pro-apoptotic protein Bax and Fas (P < 0.01). CONCLUSIONS: Dietary folic acid supplementation diminishes the cardiac myocyte apoptosis in streptozotocin-induced diabetes. The apoptosis suppression is accompanied by an increase in the expression of Bcl-2 and a decrease in Bax and Fas.