Cytotoxic activity of naphthoquinones with special emphasis on juglone and its 5-O-methyl derivative |
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Authors: | Raquel Carvalho Montenegro Ana Jérsia Araújo María Teresa Molina José Delano Barreto Marinho Filho Danilo Damasceno Rocha Eulogio Lopéz-Montero Marília OF Goulart ES Bento Ana Paula Nunes Negreiros Alves Cláudia Pessoa Manoel Odorico de Moraes Letícia Veras Costa-Lotufo |
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Institution: | 1. Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Campus do Porangabussu, Caixa Postal 3157, Fortaleza, Ceará, 60430-270, Brazil;2. Instituto de Química Médica – Consejo Superior de Investigaciones Científicas (CSIC), 28006 Madrid, Spain;3. Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Tabuleiro do Martins, Maceió, Alagoas, 57072-970, Brazil;4. Departamento de Odontologia Clínica, Universidade Federal de Ceará, Fortaleza, Ceará, Brazil |
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Abstract: | 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 IC50 values in the range of 0.31 (1.7 μM) in HL-60 to 0.88 μg/mL (4.7 μM) in SF-295 and IC50 of 0.69 μg/mL (3.7 μM) against PBMC. With the introduction of a bromo-substituent in position 2 or 3 of juglone, the IC50 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. |
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