Acta Pharmacologica Sinica (2010) 31: 259–264; doi: 10.1038/aps.2009.198

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

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 (doxorubicin-resistant) 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.

Keywords: apoptosis; cytotoxicity; drug resistance; MCF-7; tryptanthrin