title: BX795, a TBK1 inhibitor, exhibits antitumor activity in human oral squamous cell carcinoma through apoptosis induction and mitotic phase arrest.
abstract: TANK-binding kinase 1 (TBK1), a member of IκB Kinase (IKK)-related kinases, plays a role in regulating innate immunity, inflammation and oncogenic signaling. This study aims to investigate the role of BX795, an inhibitor of TBK1, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antitumor effects and mechanisms of BX795 were assessed by MTT assays, flow cytometry, Western blotting, and confocal microscopy. BX795 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound caused apoptosis as evidenced by PARP cleavage, the presence of pyknotic nuclei in the TUNEL assay, and fragmented DNA tails in the Comet assay. BX795 inhibits Akt and NF-κB signaling, arrests cells in the mitotic phase, and increases generation of autophagy in oral cancer cells. Interestingly, the antiproliferative activity of BX795 does not correlate with TBK1 protein expression level in OSCC cells. We propose that the TBK1-independet effect is related to mitotic phase arrest. Pleiotropic anticancer activity with relative sparing of normal oral keratinocytes underscores the potential value of BX795 and warrants its further study in oral squamous cell carcinoma therapy.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan; School of Medicine, China Medical University, Taichung 40447, Taiwan.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Cancer Center, China Medical University Hospital, Taichung 40447, Taiwan; School of Medicine, China Medical University, Taichung 40447, Taiwan.
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.affiliation: Department of Chemistry, Shree M. & N. Virani Science College, Saurashtra University, Rajkot, Gujarat 360005, India.
authors.forename: Naval P
authors.initials: NP
authors.lastname: Kapuriya
authors.affiliation: Department of Dental Hygiene, China Medical University, Taichung 40447, Taiwan.
authors.forename: Tzong-Ming
authors.initials: TM
authors.lastname: Shieh
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 40447, Taiwan.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 40447, Taiwan.
authors.forename: Chia-Yung
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Charles River Laboratories, Preclinical Services, Spencerville, OH 45887, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Sargeant
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 40447, Taiwan. Electronic address: columnster@gmail.com.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009062:Mouth Neoplasms / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C579675:BX795; D010750:Phosphoproteins; D011743:Pyrimidines; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C403191:TBK1 protein, human; D051550:I-kappa B Kinase
keywords: Autophagy; BX795; Cell cycle; Oral cancer; TBK1