title: Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis.
abstract: Sorafenib (SOR) is a promising treatment for advanced hepatocellular carcinoma (HCC). However, the precise mechanisms of toxicity and drug resistance have not been fully explored and new strategies are urgently needed for HCC therapy. Meloxicam (MEL) is a selective cyclooxygenase-2 (COX-2) inhibitor which elicits antitumor effects in human HCC cells. In the present study, we investigated the interaction between MEL and SOR in human SMMC‑7721 cells and the role endoplasmic reticulum (ER) stress exerts in the combination of SOR with MEL treatment-induced cytotoxicity. Our results revealed that the combination treatment synergistically inhibited cell proliferation and enhanced apoptosis. Furthermore, the combination treatment enhanced ER stress-related molecules which involved in SMMC-7721 cell apoptosis. GRP78 knockdown by siRNA or co-treatment with MG132 significantly increased this combination treatment-induced apoptosis. In addition, we found that the combination treatment suppressed tumor growth by way of activation of ER stress in in vivo models. We concluded that the combination of SOR with MEL treatment-induced ER stress, and eventually apoptosis in human SMMC-7721 cells. Knockdown of GRP78 using siRNA or proteosome inhibitor enhanced the cytotoxicity of the combination of SOR with MEL-treatment in SMMC-7721 cells. These findings provided a new potential treatment strategy against HCC.
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiu
authors.affiliation: Department of General Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, P.R. China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Honglong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Zongzhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077239:Meloxicam; D051379:Mice; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000378:metabolism; D000077157:Sorafenib; D013843:Thiazines / Q000008:administration & dosage* / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010671:Phenylurea Compounds; D013843:Thiazines; D013844:Thiazoles; D009536:Niacinamide; D000077157:Sorafenib; D000077239:Meloxicam