Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines
Journal
Acta Pharmacologica Sinica
Journal Volume
31
Journal Issue
2
Pages
259-264
Date Issued
2010
Author(s)
Abstract
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-G 1 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. ? 2010 CPS and SIMM All rights reserved.
Subjects
Apoptosis; Cytotoxicity; Drug resistance; MCF-7; Tryptanthrin
SDGs
Other Subjects
6,12 dihydro 6 (dicyanomethylene) 12 oxoindolo[2,1 b]quinazoline derivative; acid anhydride; antineoplastic agent; caspase 3; caspase 7; DNA; doxorubicin; etoposide; Fas antigen; Fas ligand; isatin; malononitrile; quinazoline derivative; tryptanthrin derivative; unclassified drug; verapamil; antineoplastic activity; apoptosis; article; cancer cell culture; cell assay; cell cycle arrest; cell proliferation; cell strain MCF 7; chemosensitization; competitive inhibition; controlled study; DNA fragmentation; drug cytotoxicity; drug effect; drug mechanism; drug structure; drug synthesis; enzyme activation; enzyme activity; enzyme assay; HeLa cell; human; human cell; multidrug resistance; polymerization; Western blotting; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Indolequinones; Quinazolines
Type
journal article