Mukherjee, Asama and Dutta, Sushanta and Shanmugavel, Muthiah and Mondhe, Dilip M and Sharma, Parduman R and Singh, Shashank K and Saxena, Ajit K and Sanyal, Utpal
(2010)
6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis.
Journal of Experimental & Clinical Cancer Research, 29 (1).
p. 175.
ISSN 1756-9966
Abstract
Background: Anticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are
well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl)
naphthalimides (compounds 1a-j) were evaluated as antitumor agents.
Methods: Compounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results
were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of
caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time
intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following
treatment with 8 μM concentration of compounds 1d and 1i were studied.
Results: 6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum
activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any
cytotoxicity against human PBMC (IC50 value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating upregulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle
respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was
mediated by activation of both caspase 3 and 6. Light and transmission electron microscopic studies corroborated
its apoptosis inducing efficacy at a concentration of 10 μM in MOLT-4 cells. Its apoptosis induction was also observed in HL-60 cells to an extent much greater than well known apoptosis inducing agents as camptothecin and cis-platin at 10 μM concentration each. It significantly inhibited DNA and RNA synthesis in S-180.
Conclusions: In essence, compound 1i showed potential as an antitumor agent.
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