3-7-dioxolanosta-8-24-dien-26-oic-acid and Carcinoma--Non-Small-Cell-Lung

The incidence and mortality of lung cancer are the highest among cancer-related deaths. However, the long-term use of currently available cytotoxic drugs can increase genetic alterations in cancer cells and cause drug-resistance, which significantly limits their usage. Since current systemic treatment options are limited, effective chemotherapeutic agents are urgently needed for non-small cell lung cancer (NSCLC) treatment. In this study, we demonstrated that ganoderic acid DM (GA-DM) could increase apoptosis in A549 and NCI-H460 NSCLC cells. GA-DM treatment decreased the protein expression levels of Bcl-2 and increased the expression levels of Bax, cleaved caspase-3 and cleaved PRAP. Furthermore, GA-DM could promote autophagic flux, and the cytotoxic effect against cancer cells of GA-DM was significantly inhibited by targeted suppression of autophagy, suggesting that autophagy contributed to GA-DM-induced cell death in NSCLC. Moreover, GA-DM clearly induced autophagy by inactivating the PI3K/Akt/mTOR pathway. When overexpression of Akt reactivated Akt/mTOR pathway in A549 or NCI-H460 cells, the increase of autophagy related marker LC3B-II and apoptosis related protein cleaved PARP and cleaved caspase 3 and the ration of apoptotic cells by GA-DM was reversed, suggesting that GA-DM promoted autophagy and apoptosis by inhibiting Akt/mTOR pathway-mediated autophagy induction. In conclusion, our study indicated that GA-DM can induce autophagic apoptosis in NSCLC by inhibiting Akt/mTOR activity. (209 words).

Topics: Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Line, Tumor; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Triterpenes