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: Wen-Liang Lo, Pen-Yuan Chu, Tsung-Heng Lee, Tsann-Long Su, Yueh Chien, Yi-Wei Chen, Pin-I Huang, Ling-Ming Tseng, Pang-Hsien Tu, Shou-Yen Kao, Jeng-Fan Lo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 13 Issue 3 Pg. 3277-3290 ( 2012) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 22489152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• BO-1051
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• Nitrogen Mustard Compounds
• Protein Kinases
• Checkpoint Kinase 2
• Checkpoint Kinase 1

Topics

• Animals
• Antineoplastic Agents, Alkylating (administration & dosage, pharmacology)
• Autophagy (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects)
• Checkpoint Kinase 1
• Checkpoint Kinase 2 (metabolism)
• DNA Damage
• Dose-Response Relationship, Drug
• Female
• Gingiva (cytology, drug effects)
• Humans
• Mice
• Mice, Nude
• Microtubule-Associated Proteins (metabolism)
• Mouth Neoplasms (drug therapy, metabolism, pathology)
• Nitrogen Mustard Compounds (administration & dosage, pharmacology)
• Phosphorylation
• Protein Kinases (metabolism)
• Xenograft Model Antitumor Assays