Cytotoxic activity of naphthoquinones with special emphasis on juglone and its 5-O-methyl derivative.
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 72h of incubation. 5-Methoxy-1,4-naphthoquinone was the most active compound, showing IC(50) values in the range of 0.31 (1.7microM) in HL-60 to 0.88microg/mL (4.7microM) in SF-295 and IC(50) of 0.69microg/mL (3.7microM) 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.
Montenegro
Raquel Carvalho
RC
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Campus do Porangabussu, Caixa Postal 3157, Fortaleza, Ceará, 60430-270, Brazil. rc_montenegro@yahoo.com.br <rc_montenegro@yahoo.com.br>
Araújo
Ana Jérsia
AJ
Molina
María Teresa
MT
Marinho Filho
José Delano Barreto
JD
Rocha
Danilo Damasceno
DD
Lopéz-Montero
Eulogio
E
Goulart
Marília O F
MO
Bento
E S
ES
Alves
Ana Paula Nunes Negreiros
AP
Pessoa
Cláudia
C
de Moraes
Manoel Odorico
MO
Costa-Lotufo
Letícia Veras
LV
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009285:Naphthoquinones / Q000737:chemistry* / Q000633:toxicity; D010718:Phosphatidylserines / Q000378:metabolism
D000970:Antineoplastic Agents; D009285:Naphthoquinones; D010718:Phosphatidylserines; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; C005134:juglone