title: A combined DNA-affinic molecule and N-mustard alkylating agent has an anti-cancer effect and induces autophagy in oral cancer cells.
abstract: Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N-mustard, play an important role in cancer drug development. BO-1051 is a new 9-anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC(50) in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future.
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Dentistry, Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11217 Taiwan.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
authors.affiliation: Laryngology and Head and Neck Surgery, Department of Otolaryngology, Taipei Veterans General Hospital, Taipei 11217 Taiwan.
authors.forename: Pen-Yuan
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Department of Dentistry, Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11217 Taiwan.
authors.forename: Tsung-Heng
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217 Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217 Taiwan.|Cancer Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217 Taiwan.|Cancer Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217 Taiwan.|Department of Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Dentistry, Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11217 Taiwan.
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005881:Gingiva / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; C557045:BO-1051; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009588:Nitrogen Mustard Compounds; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1