title: Combined treatment of XIAP-targeting shRNA and celecoxib synergistically inhibits the tumor growth of non‑small cell lung cancer cells in vitro and in vivo.
abstract: X-linked inhibitor of apoptosis protein (XIAP) has been shown to be highly expressed in lung cancer, but not in normal lung tissue, which makes it an attractive target for lung cancer treatment. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, is in wide clinical use for the treatment and prevention of non-small cell lung cancer (NSCLC). Therefore, in our study, we combined short hairpin RNA (shRNA) targeted to XIAP (XIAP-shRNA) with CXB and tested the effects of this combination on lung cancer cells to identify more effective therapeutics against lung cancer. An XIAP-shRNA plasmid was constructed and transfected into the A549 NSCLC cell line. The cells were then treated with CXB and XIAP-shRNA alone or in combination for indicated time periods, and the treatments were assessed for their effects on cell proliferation, apoptosis, migration, invasion and receptor signaling using the MTT, TUNEL, wound healing and Matrigel invasion assays and western blotting, respectively. In addition, an NSCLC xenograft model was prepared to observe tumor growth. It was found that both CXB and XIAP‑shRNA significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in vitro, as well as suppressed tumor growth in vivo. Moreover, the combination of the agents significantly enhanced these effects compared to the single agent treatments. We also found that the combination treatment significantly suppressed constitutive phosphorylation of PI3K and AKT, which may contribute to the inhibition of tumor growth. These findings suggest that the combination of XIAP‑shRNA and CXB is a promising drug candidate for the treatment of NSCLC.
authors.affiliation: Department of Thoracic Surgery, The First Hospital of Jilin University, Chaoyang, Changchun, Jilin 130021, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, The First Hospital of Jilin University, Chaoyang, Changchun, Jilin 130021, P.R. China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery, The First Hospital of Jilin University, Chaoyang, Changchun, Jilin 130021, P.R. China.
authors.forename: Kaizhong
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, The First Hospital of Jilin University, Chaoyang, Changchun, Jilin 130021, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000068579:Celecoxib