Laboratório de Imunologia Tumoral, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Invest New Drugs. 2010 Apr;28(2):139-44. doi: 10.1007/s10637-009-9231-y. Epub 2009 Mar 4.
The pentacyclic 1,4-naphthoquinones 1a-d were cytotoxic (IC(50) approximately 2-7 microM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell lines were highly insensitive to lapachol (2) and alpha-lapachone (3). Mitomycin-C inhibited cell proliferation at concentrations as low as 0.5 microM. The low toxicity against lymphocytes activated by phytohemagglutinin shows that these compounds are selective for the cancer cells studied. Previous data suggest that these compounds (1a-d) can be bioactivated in situ by reduction followed by rearrangement leading to enones, which are powerful alkylating agents. In contrast, lapachol (2) and beta-lapachone (3), which cannot be bioactivated by reduction, showed little activity against the same cell lines.
五环[1,4]萘醌 1a-d 对人白血病细胞系 K562（氧化应激抗性）、Lucena-1（MDR 表型）和 Daudi 具有细胞毒性（IC50 约为 2-7 μM）。从患者中获得的新鲜白血病细胞，有些具有 MDR 表型，也对这些化合物敏感。五环[1,4]萘醌 1a 和 1c 通过流式细胞术确定在白血病患者的细胞中诱导凋亡细胞死亡。相反，细胞系对拉帕醌（2）和α-拉帕醌（3）高度不敏感。丝裂霉素 C 在低至 0.5 μM 的浓度下即可抑制细胞增殖。对植物血凝素激活的淋巴细胞的低毒性表明，这些化合物对研究的癌细胞具有选择性。先前的数据表明，这些化合物（1a-d）可以通过还原随后重排原位生物激活，生成烯酮，烯酮是一种强大的烷化剂。相比之下，不能通过还原生物激活的拉帕醌（2）和β-拉帕醌（3）对相同的细胞系几乎没有活性。
