hyperoside and Carcinoma--Non-Small-Cell-Lung

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism that accounts for EGFR‑TKI (tyrosine kinase inhibitor) resistance of non‑small cell lung cancer (NSCLC). High expense and acquired resistance weaken support for the use of osimertinib for T790M‑positive NSCLC treatment, and limit the efficacy and application of this drug. Hyperoside, a flavonol glycoside compound, extracted from Hypericum perforatum, has been reported to inhibit the growth of a variety of tumors. The present study aimed to investigate the role of hyperoside in treating NSCLC with T790M mutations, and to elucidate the underlying molecular mechanisms. Cell viability assays, apoptosis analysis, reverse transcription‑quantitative PCR, western blot analysis, animal experiments and immunohistochemistry were performed to examine the anticancer activity of hyperoside. Hyperoside inhibited the proliferation and induced the apoptosis of T790M‑positive NSCLC cells. Hyperoside upregulated forkhead box protein O1 (FoxO1) expression and downregulated the level of long non‑coding RNA (lncRNA) colon cancer associated transcript 1 (CCAT1) in T790M‑positive NSCLC cells. In the in vivo study, hyperoside inhibited the growth of T790M‑positive NSCLC xenografts. In conclusion, hyperoside inhibited proliferation and induced apoptosis by upregulating FoxO1 via CCAT1 in T790M‑positive NSCLC both in vitro and in vivo, suggesting that hyperoside is a novel candidate for T790M‑positive NSCLC treatment.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Forkhead Box Protein O1; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Mutation; Quercetin; RNA, Long Noncoding; Up-Regulation; Xenograft Model Antitumor Assays

Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside found in plants of the genera Hypericum and Crataegus, which exhibits anticancer, anti-oxidant, and anti-inflammatory activities. In this study we investigated whether autophagy was involved in the anticancer mechanisms of hyperoside in human non-small cell lung cancer cells in vitro.. Human non-small cell lung cancer cell line A549 was tested, and human bronchial epithelial cell line BEAS-2B was used for comparison. The expression of LC3-II, apoptotic and signaling proteins was measured using Western blotting. Autophagosomes were observed with MDC staining, LC3 immunocytochemistry, and GFP-LC3 fusion protein techniques. Cell viability was assessed using MTT assay.. Hyperoside (0.5, 1, 2 mmol/L) dose-dependently increased the expression of LC3-II and autophagosome numbers in A549 cells, but had no such effects in BEAS-2B cells. Moreover, hyperoside dose-dependently inhibited the phosphorylation of Akt, mTOR, p70S6K and 4E-BP1, but increased the phosphorylation of ERK1/2 in A549 cells. Insulin (200 nmol/L) markedly enhanced the phosphorylation of Akt and decreased LC3-II expression in A549 cells, which were reversed by pretreatment with hyperoside, whereas the MEK1/2 inhibitor U0126 (20 μmol/L) did not blocked hyperoside-induced LC3-II expression. Finally, hyperoside dose-dependently suppressed the cell viability and induced apoptosis in A549 cells, which were significantly attenuated by pretreatment with the autophagy inhibitor 3-methyladenine (2.5 mmol/L).. Hyperoside induces both autophagy and apoptosis in human non-small cell lung cancer cells in vitro. The autophagy is induced through inhibiting the Akt/mTOR/p70S6K signal pathways, which contributes to anticancer actions of hyperoside.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Quercetin; Signal Transduction