title: Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells.
abstract: Honokiol (HNK), a potential antitumor compound, has been widely studied in recent years. It induces apoptosis and affects autophagy in cancer cells, yet the mechanism of its antitumor efficacy remains obscure. Chloroquine (CQ), an autophagy inhibitor, is often applied to sensitize antitumor drugs in clinical trials. Here, we investigated the antitumor effect of HNK or CQ alone or in combination in non-small cell lung cancer (NSCLC) cells. Using an experimental approach, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or sulforhodamine B (SRB) was used to determine the cytotoxicity of the agents. The expression levels of proteins were detected by western blotting. Apoptosis was examined via Annexin V-FITC and PI staining. H460 cell xenografts in nude mice were used to study the effects of HNK and/or CQ in vivo. Transfection with siRNA was applied to knock down cathepsin D. The results demonstrated the enhanced effects of HNK combined with CQ on the inhibition of proliferation, induction of apoptosis in vitro and the reduction in growth in vivo. It was confirmed that HNK and/or CQ triggered apoptosis via a caspase-dependent manner. Furthermore, HNK significantly increased the expression of p62 and LC3-Ⅱ in the A549 and H460 cells and inhibited autophagy and induced apoptosis in a cathepsin D-involved manner. In conclusion, an enhanced antitumor effect was demonstrated following treatment with HNK combined with CQ by inhibiting autophagy and inducing apoptosis via a caspase-dependent and cathepsin D-involved manner. This combination may be a novel and useful antitumor approach for chemotherapy in NSCLC.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Chongwen, Beijing 100050, P.R. China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lv
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Chongwen, Beijing 100050, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Chongwen, Beijing 100050, P.R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Chongwen, Beijing 100050, P.R. China.
authors.forename: Shu-Zhen
authors.initials: SZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000008:administration & dosage*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000008:administration & dosage*; D051379:Mice; D009363:Neoplasm Proteins / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D002738:Chloroquine; D017705:Lignans; D009363:Neoplasm Proteins; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols