Induction of apoptosis in human cancer cell lines by diospyrin, a plant-derived bisnaphthoquinonoid, and its synthetic derivatives

• Published in: Cancer letters Vol. 188; no. 1; pp. 85 - 93
• Main Authors: Chakrabarty, Sutapa, Roy, Madhumita, Hazra, Banasri, Bhattacharya, R.K.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 15-12-2002; Elsevier; Elsevier Limited
• Subjects: Antibiotics; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Bisnaphthoquinonoid; Cancer; Cancer therapies; Caspase 3; Caspase 8; Caspase 9; Caspase activity; Caspases - metabolism; Cell Division - drug effects; Chemotherapy; Cytotoxicity; Deoxyribonucleic acid; Derivatives; Diospyrin; Diospyros - chemistry; DNA; DNA fragmentation; Humans; Leukemia; Medical sciences; Microscopy, Fluorescence; Naphthoquinones - pharmacology; Neoplasms - drug therapy; Pharmacology. Drug treatments; Plant Bark - chemistry; Studies; Tumor cells; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - pathology; Bisnaphthoquinonoid; Diospyrin; Caspase activity; Tumor cells; DNA fragmentation; Apoptosis; Antineoplastic agent; Human; Enzyme; Caspase; Malignant tumor; In vitro; Biological activity; Bisnaphlhoquinonoid; Peptidases; Enzymatic activity; Cell death; Established cell line; Plant origin; Hydrolases; Mechanism of action
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(02)00494-9

Diospyrin, a bisnaphthoquinonoid natural product, and three synthetic derivatives have been tested for their action in four human cancer cell lines: acute myeloblastic leukemia (HL-60), chronic myelogenic leukemia (K-562), breast adenocarcinoma (MCF-7) and cervical epithelial carcinoma (HeLa). In cells grown in appropriate media several derivatives elicited cytotoxicity as assessed by Trypan Blue dye exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide reduction and DNA synthesis. Diethyl ether derivative (D7) was most effective in this regard while the parent compound diospyrin (D1) was least active (D7>D3>D2>D1). D7 was not cytotoxic toward normal human lymphocytes, suggesting its action is specific for tumor cells. On microscopic examination D7-treated cells exhibited characteristic morphological features of apoptosis, such as cell shrinkage and formation of apoptotic bodies. Fluorescent staining with propidium iodide revealed distinct chromatin condensation and nuclear fragmentation. The apoptotic index paralleled cytotoxic parameters, and fragmented DNA extracted free of genomic DNA displayed on gel electrophoresis a typical ladder pattern. D7-induced apoptosis was mediated via activation of caspase 3 and caspase 8.