title: Cedrol induces autophagy and apoptotic cell death in A549 non-small cell lung carcinoma cells through the P13K/Akt signaling pathway, the loss of mitochondrial transmembrane potential and the generation of ROS.
abstract: The objective of the present study was to determine the anticancer effects of cedrol in A549 human non-small cell lung cancer cells by examining the effects of cedrol on apoptosis induction, the phosphatidylinositol 3'-kinase (PI3K)/Akt signaling pathway, autophagy, reactive oxygen species (ROS) generation and mitochondrial transmembrane potential (MTP). The anticancer effects of cedrol were examined using A549 human lung carcinoma cells as an in vitro model. Cell viability was determined using MTT and lactate dehydrogenase (LDH) assays, and an inverted phase contrast microscope was used to examine the morphological changes in these cells. Cedrol‑triggered autophagy was confirmed by transmission electron microscopy (TEM) analysis of the cells, as well as by western blot analysis of microtubule-associated protein light-chain 3 (LC3)B expression. Intracellular ROS generation was measured by flow cytometry using 5-(6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CM-DCFH2-DA) staining and MTP was measured using flow cytometry. The results demonstrated that cedrol reduced cell viability and induced cell apoptosis in a dose-dependent manner. Mechanistic evaluations indicated that cedrol induced apoptosis by reducing the MTP and by decreasing the levels of phosphorylated (p-)PI3K and p-Akt. Cedrol induced autophagy, which was confirmed by TEM analysis, by increasing intracellular ROS formation in a concentration-dependent manner, which was almost completely reversed by N-acetyl-L-cysteine (NAC) and tocopherol. Taken together, these findings reveal that cedrol inhibits cell proliferation and induces apoptosis in A549 cells through mitochondrial and PI3K/Akt signaling pathways. Our findings also reveal that cedrol induced pro-death autophagy by increasing intracellular ROS production.
authors.affiliation: Department of Radiotherapy, Weifang Yidu Central Hospital, Weifang Medical University, Weifang, Shandong 262500, P.R. China.
authors.forename: Shi-Yi
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Department of Radiotherapy, Weifang Yidu Central Hospital, Weifang Medical University, Weifang, Shandong 262500, P.R. China.
authors.forename: Xue-Bo
authors.initials: XB
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Weifang Yidu Central Hospital, Weifang Medical University, Weifang, Shandong 262500, P.R. China.
authors.forename: Sheng-Guang
authors.initials: SG
authors.lastname: Hou
authors.affiliation: Department of Radiotherapy, Weifang Yidu Central Hospital, Weifang Medical University, Weifang, Shandong 262500, P.R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Surgical Oncology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China.
authors.forename: Yi-Ran
authors.initials: YR
authors.lastname: Shi
authors.affiliation: Department of Radiotherapy, Weifang Yidu Central Hospital, Weifang Medical University, Weifang, Shandong 262500, P.R. China.
authors.forename: Song-Sen
authors.initials: SS
authors.lastname: Lin
mesh_terms: D000072283:A549 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081223:Polycyclic Sesquiterpenes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000081223:Polycyclic Sesquiterpenes; D017382:Reactive Oxygen Species; D013729:Terpenes; C078669:cedrol; D007770:L-Lactate Dehydrogenase; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000111:Acetylcysteine