RESUMEN
OBJECTIVE: Merlin is encoded by Neurofibromatosis type 2 gene (NF-2), a tumor suppressor gene, which causes some multiple tumors forming disease of the nervous system in case of function loss. Bioinformatics analysis suggested that patients with NF-2 mutation had a worse prognosis, while it was associated with PI3K/mTOR activation, implying abnormal apoptosis in NF-2 mutation related tumors. Hence, we supposed that the inhibitors of PI3K/mTOR pathway might play a role in suppressing the tumor proliferation. MATERIALS AND METHODS: Two representative NF-2 mutation tumor model of NCI-H2452 and HEI193 cell lines were adopted, while two PI3K/mTOR pathway inhibitors Trametinib and Vistusertib were chosen to study the proliferation and apoptosis of the tumor cells. RESULTS: CCK8 cell counting experiment showed that both Trametinib and Vistusertib could inhibit the proliferation of NCI-H2452 cell in vitro, while the combination of Trametinib and Vistusertib was more significant. Flow cytometry results showed that both Trametinib and Vistusertib could enhance apoptosis of NCI-H2452 cell in vitro, while the combination of Trametinib and Vistusertib was more significant. Similar results were also achieved for HEI193 cell lines. In vivo tumorigenicity experiments demonstrated that the tumor volume and weight were significantly decreased by both Trametinib and Vistusertib, while their combination had the most significant effect. Western blot results demonstrated that both Trametinib and Vistusertib could inhibit PI3K/mTOR /MEK pathway and enhance the expression of merlin. CONCLUSIONS: We found that PI3K/mTOR inhibitor could decrease the proliferation of NF-2 mutation tumor cell lines by enhancing apoptosis, while the combination of two drugs might have a better effect.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Mesotelioma/tratamiento farmacológico , Morfolinas/farmacología , Neurofibromina 2/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacología , Pirimidinas/farmacología , Pirimidinonas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzamidas/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Biología Computacional , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mesotelioma/metabolismo , Mesotelioma/patología , Morfolinas/química , Mutación , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Pirimidinas/química , Pirimidinonas/química , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
We investigated the role of insulin-like growth factor-1 (IGF-1) in spontaneously hypertensive rats with erectile dysfunction. Firstly, we evaluated intracavernous pressure. The bioavailability of IGF-1 at both mRNA and protein levels were measured by quantitative real-time PCR and Western blot respectively. Then, cavernous cyclic guanosine monophosphate concentrations were detected by enzyme-linked immunosorbent assay. The cavernosal pressure was significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). Cavernous IGF-1 bioavailability and the concentrations of cavernous cyclic guanosine monophosphate were both significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). This study suggests that an obvious decrease in cavernous IGF-1 levels might play an important role in spontaneously hypertensive rats with erectile dysfunction.
