A Combined DNA-Affinic Molecule and N-Mustard Alkylating Agent Has an Anti-Cancer Effect and Induces Autophagy in Oral Cancer Cells

International Journal of Molecular Sciences

Wen-Liang Lo⁵  Pen-Yuan Chu⁴  Tsung-Heng Lee²  Tsann-Long Su¹  Yueh Chien³  Yi-Wei Chen³  Pin-I Huang³  Ling-Ming Tseng³  Pang-Hsien Tu¹  Shou-Yen Kao⁵ 

[1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; E-Mails:;Department of Dentistry, Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11217 Taiwan; E-Mail:;Institute of Clinical Medicine, National Yang-Ming University, Taipei 11217 Taiwan; E-Mails:;Laryngology and Head and Neck Surgery, Department of Otolaryngology, Taipei Veterans General Hospital, Taipei 11217 Taiwan; E-Mail:;Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan; E-Mail:

关键词: BO-1051;    AVO;    autophagy;    cell cycle;    checkpoint kinases;   

DOI  :  10.3390/ijms13033277

来源: mdpi

【 摘 要 】

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 IC₅₀ 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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.