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.
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>
Raquel Carvalho
RC
Montenegro
Ana Jérsia
AJ
Araújo
María Teresa
MT
Molina
José Delano Barreto
JD
Marinho Filho
Danilo Damasceno
DD
Rocha
Eulogio
E
Lopéz-Montero
Marília O F
MO
Goulart
E S
ES
Bento
Ana Paula Nunes Negreiros
AP
Alves
Cláudia
C
Pessoa
Manoel Odorico
MO
de Moraes
Letícia Veras
LV
Costa-Lotufo
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