Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 184, Issue 3, Pages 439-448Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2010.01.041
Keywords
Naphthoquinones; Juglone; Cytotoxicity; Apoptosis; Caspases; Cell cycle
Funding
- CNPq
- CSIC-CNPq
- DGICYT Spain [BQU2003-00813, SAF2006-04698]
- CAPES
- FUNCAP
- FINEP
- BNB/FUNDECI
- FAPEAL
- MCT/DECIT
- MCT/MS/Neoplasias
- IM-INOFAR/CNPq
- PRONEX/FAPEAL
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The cytotoxicity of nine naphthoquinones (NQ) was assayed against HL-60 (leukaemia), MDA-MB-435 (melanoma), SF-295 (brain) and HCT-8 (colon), all human cancer cell lines, and peripheral blood mononuclear cells (PBMC), as representatives of normal cells, after 72 h of incubation. 5-Methoxy-1,4-naphthoquinone was the most active compound, showing IC(50) values in the range of 0.31 (1.7 mu M) in HL-60 to 0.88 mu g/mL (4.7 mu M) in SF-295 and IC(50) of 0.69 mu g/mL (3.7 mu M) against PBMC. With the introduction of a bromo-substituent in position 2 or 3 of juglone, the IC(50) significantly decreased, regardless of the position on the NQ moiety. However, compared with juglone methyl ether, the halogen substitution decreased the activity. To further understand the mechanism underlying the cytotoxicity of 5-methoxy-1,4-naphthoquinone, studies involving DNA fragmentation, cell cycle analysis, phosphatidyl serine externalization, mitochondrial depolarization and activation of caspases 8 and 3/7 were performed in HL-60 cell line, using doxorubicin as a positive control. The results indicate that the cytotoxic 5-methoxy-1,4-naphthoquinone activates caspases 8 and 3/7 and thus induces apoptosis independent of mitochondria. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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