A novel antitubulin agent, DPQZ, induces cell apoptosis in human oral cancer cells through Ras/Raf inhibition and MAP kinases activation

作者：Hour Mann Jen; Lee Kun Tsung; Wu Yang Chang; Wu Chi Yu; You Bang Jau; Chen Tai Lin; Lee Hong Zin^*

来源：Archives of Toxicology, 2013, 87(5): 835-846.

DOI：10.1007/s00204-012-0991-3

• 6-(N,N-Dimethylamino)-2-(naphthalene-1-yl)-4-quinazolinone
• Human oral cancer HSC-3 cells
• Antitubulin agent
• Apoptosis
• MAP kinases
• Ras/Raf

6-(N,N-Dimethylamino)-2-(naphthalene-1-yl)-4-quinazolinone (DPQZ)-induced apoptosis was accompanied by the characteristics of DNA fragmentation and phosphatidylserine externalization in human oral cancer HSC-3 cells. The IC50 (half maximal inhibitory concentration) value of DPQZ is about 0.25 mu M at 24 h. The interference in the dynamics of tubulin and cell division of DPQZ, like vinblastine (0.01 mu M), has been proven in this study. Treatment of HSC-3 cells with DPQZ resulted in many of mitotic cells with multipolar spindles. Up-regulation of MAP kinases, such as ERK, JNK, and p38, mediated by DPQZ appears to be involved in DPQZ-induced apoptosis in HSC-3 cells. It is worthy of note that the expression of Ras and c-Raf that lie upstream of ERK were inhibited by DPQZ. In addition, the DPQZ-induced cell death was attenuated by JNK inhibitor SP600125 (3 or 10 mu M), not by the ERK or p38 inhibitors. JNK inhibitor abolished the DPQZ-induced increase in the phosphorylation of Bcl-2 and the protein levels of proform caspase-3, caspase-8, and caspase-9, indicating that JNK is an upstream activator of Bcl-2 and caspase family members and plays a key role in DPQZ-induced HSC-3 cell apoptosis. We also attempted to develop an anticancer drug that is designed to kill rapidly dividing cancer cells while causing less damage to normal cells. The DPQZ-induced cytotoxicity against human gingival fibroblasts was less than that against HSC-3 cells. Our work provides a new strategy and mechanism for developing anticancer drug and may contribute to clinical anticancer drug discovery and application.

• 出版日期2013-5
• 单位中国医科大学