Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines  

作　　者：Sung-tsai YU Ji-wang CHERN Tzer-ming CHEN Yi-fan CHIU Hui-ting CHEN Yen-hui CHEN 

机构地区：[1]Graduate Institute of Pharmaceutical Sciences Nation Taiwan University, No i Sec 1, Jen-Ai Road, Taipei 10051, Taiwan, China [2]Graduate Institute of Clinical Pharmacy, Nation Taiwan University, No i Sec 1, Jen-Ai Road, Taipei 10051, Taiwan, China [3]Department of Obstetrics and Gynecology, Nation Taiwan University Hospital, No 7 Chung San South Road, Taipei 10051, Taiwan, China

出　　处：《Acta Pharmacologica Sinica》2010年第2期259-264,共6页中国药理学报（英文版）

摘　　要：Aim： To evaluate the effects and elucidate the mechanisms of a series of indoloquinazolines as novel anticancer agents. Methods： Condensation of the substituted isatoic anhydride with the substituted isatin was performed to prepare compounds 1-4, followed by adding malononitrile to prepare compounds 5-7. Cytotoxicity was measured by MTT assays. Apoptosis induction was evaluated using DNA fragmentation, cell cycle assay, caspase 3/7 activity and Western blot. Results： Compounds 3, 4, and 5 display cytotoxicity against MCF-7, HeLa, SKOV3, and A498 cancer cells. DNA ladders appear in cells treated with compounds 3, 4, and 5. Within those, compound 4 exhibits the greatest activity in regards to sub-G1 accumulations in the cell cycle and the activation of caspase-3/7. Furthermore, Fas and Fas ligand levels are elevated by compound 4, implying that the apoptosis is in part mediated through the signals. On the other hand, compounds 1 and 7 display chemosensitizing activity since cytotoxicity of doxorubicine and etoposide is enhanced in combination with compound 1 and 7, respectively, in MCF-7/adr （doxorubicinresistant） and MCF-7/vp （etoposide-resistant）. Conclusion： The cytotoxicity of indoloquinazolines is structure-dependent rather than cell type-dependent due to the similar degree of cytotoxicity induced by the individual compounds in all four cell lines. Further modification of the tryptanthrin skeleton is important to develop novel anticancer agents bearing either cytotoxicity against MCF-7 cells or drug resistance reversal in MCF-7/adr and MCF-7/vp.Aim： To evaluate the effects and elucidate the mechanisms of a series of indoloquinazolines as novel anticancer agents. Methods： Condensation of the substituted isatoic anhydride with the substituted isatin was performed to prepare compounds 1-4, followed by adding malononitrile to prepare compounds 5-7. Cytotoxicity was measured by MTT assays. Apoptosis induction was evaluated using DNA fragmentation, cell cycle assay, caspase 3/7 activity and Western blot. Results： Compounds 3, 4, and 5 display cytotoxicity against MCF-7, HeLa, SKOV3, and A498 cancer cells. DNA ladders appear in cells treated with compounds 3, 4, and 5. Within those, compound 4 exhibits the greatest activity in regards to sub-G1 accumulations in the cell cycle and the activation of caspase-3/7. Furthermore, Fas and Fas ligand levels are elevated by compound 4, implying that the apoptosis is in part mediated through the signals. On the other hand, compounds 1 and 7 display chemosensitizing activity since cytotoxicity of doxorubicine and etoposide is enhanced in combination with compound 1 and 7, respectively, in MCF-7/adr （doxorubicinresistant） and MCF-7/vp （etoposide-resistant）. Conclusion： The cytotoxicity of indoloquinazolines is structure-dependent rather than cell type-dependent due to the similar degree of cytotoxicity induced by the individual compounds in all four cell lines. Further modification of the tryptanthrin skeleton is important to develop novel anticancer agents bearing either cytotoxicity against MCF-7 cells or drug resistance reversal in MCF-7/adr and MCF-7/vp.

关 键 词：apoptosis CYTOTOXICITY drug resistance MCF-7 TRYPTANTHRIN 

分 类 号：Q51[生物学—生物化学] Q959.133