sto-609 and oxadin

β,β-Dimethylacrylshikonin (DMAS), an active ingredient of Lithospermum erythrorhizon and Arnebia euchroma, possess anti-neoplasm properties. Recently, DMAS was reported to stimulate autophagy in lung adenocarcinoma cells. However, the mechanisms by which DMAS modulates autophagy. have not yet been clearly elucidated. In this study, we found that DMAS significantly elevated intracellular free calcium accumulation. This activated the CaMKKβ-AMPK-mTOR pathway, subsequently inhibited mTOR and its substrate p70s6k and 4E-BP1, eventually leading to autophagy. In addition, we demonstrated that inhibition of autophagy by BAPTA-AM or STO-609 or compound C potently enhanced DMAS-induced lung adenocarcinoma cells apoptosis and growth inhibition. Overall, our results suggested that cytoprotective autophagy was triggered by DMAS via CaMKKβ-AMPK-mTOR signaling cascade in human lung adenocarcinoma cells, meaning that combining use of DMAS and autophagy inhibitors as a novel therapeutic option for lung adenocarcinoma will be very promising.

Topics: A549 Cells; Adaptor Proteins, Signal Transducing; AMP-Activated Protein Kinases; Antineoplastic Agents, Phytogenic; Autophagy; Benzimidazoles; Boraginaceae; Calcium; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Egtazic Acid; Gene Expression Regulation, Neoplastic; Humans; Lithospermum; Methyltransferases; Naphthalimides; Naphthoquinones; Oxazines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases