RESUMEN
The present research reports a novel biological activity of indatraline, a compound clinically used as an antidepressant. We previously identified indatraline as an autophagy inducer. Autophagy is an intracellular catabolic pathway for degrading or recycling unnecessary organelles in response to cellular stress. Indatraline-mediated autophagy induction results from mTOR inhibition. The mTOR is a negative regulator of autophagy as well as a master regulator of angiogenesis. Angiogenesis defines the process by which new vessels are formed from pre-existing vascular tissues, providing nutrients to cancer cells, allowing rapid tumor progression. Accordingly, targeting angiogenesis to prevent cancer is an attractive therapeutic strategy. Here, we demonstrate that indatraline possibly acts to suppress tumor-mediated angiogenesis via downregulation of HIF-1α-mediated VEGF expression. The effects of indatraline on autophagy and angiogenesis could make it a potential drug candidate toward cancer treatment.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Indanos/farmacología , Metilaminas/farmacología , Neovascularización Patológica/prevención & control , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Autofagia/efectos de los fármacos , Hipoxia de la Célula , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Células HeLa , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Immunoblotting , Indanos/química , Metilaminas/química , Estructura Molecular , Neovascularización Patológica/metabolismo , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
Indatraline is an antidepressive agent and a non-selective monoamine transporter inhibitor that blocks the reuptake of neurotransmitters (dopamine, serotonin, and norepinephrine). In this study, we report that indatraline induces autophagy via the suppression of mTOR/S6 kinase signaling. Autophagy induction was examined by a cell-based high content screening system using LysoTracker, which was followed by monodansylcadaverine staining and transmission electron microscope observation. Indatraline increased the number of EGFP-LC3 cells expressing autophagosomes in the cytoplasm. Conversion of LC3 was further validated by immunoblotting. Indatraline induced autophagy by affecting the AMPK/mTOR/S6K signaling axis and had no influence on the PI3K/AKT/ERK signaling. Moreover, indatraline induced autophagy in smooth muscle cells (SMCs); further, it exhibited therapeutic potential for restenosis by inhibiting SMC accumulation in a rat restenosis model. These results provide new insights into the role of monoamine transporters in autophagy regulation and identify indatraline as a novel agent for inducing autophagy.