naphthoquinones and 2-methylnaphtho(2-3-b)furan-4-9-dione

2-methyl-naphtho[2,3-b]furan-4,9-dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin-C and adriamycin, the cytotoxicity of FNQ3 is often 10- to 14-fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose-dependent fashion (50% inhibitory concentration approximately 1.25 microg/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL-60 myeloid cells in the presence of either 1alpha, 25(OH)(2) dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] or all-trans-retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies.

Topics: Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Division; Dose-Response Relationship, Drug; Humans; Leukemia; Membrane Potentials; Mitochondrial Membranes; Multiple Myeloma; Naphthoquinones; Tumor Cells, Cultured

The mechanisms of the antitumor reactions of 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) to human lung adenocarcinoma A549 cells were investigated. A549 cells that received 1.25 microg/ml FNQ3 (IC(50) at 0.35 microg/ml) developed intensive mitochondrial H(2)O(2) production at 1 h. Selective structural mitochondrial swelling, alteration of mitochondrial membrane potential, and cytochrome c and caspase-9 release from the mitochondria occurred 18-24 h later. alpha-Tocopherol inhibited the alteration of both mitochondrial permeability and the leakage of procaspase-9. The caspase-9 was then activated in the cytosol. The expression of Bcl-2 oncoprotein was suppressed by FNQ3, and resulted in apoptosis. The higher dose of 5 microg/ml induced necrosis via severe mitochondrial breakage. These results showed that FNQ3 targets the mitochondria of A549 cells to produce a reactive oxygen species resulting in apoptosis and necrosis.

Topics: Adenocarcinoma; alpha-Tocopherol; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Blotting, Western; Caspase 9; Caspases; Cytochrome c Group; Cytoplasm; DNA Fragmentation; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Flow Cytometry; Genes, bcl-2; Humans; Hydrogen Peroxide; Lung Neoplasms; Membrane Potentials; Microscopy, Confocal; Microscopy, Electron; Mitochondria; Naphthoquinones; Necrosis; Permeability; Tumor Cells, Cultured

2-Methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) has been reported to be more cytotoxic to human malignant tumor cell lines than are the corresponding normal epithelial cells. Therefore, we examined the dose response of FNQ3 against human cervical cancer HeLa cells in culture. When 1.25 mg/ml FNQ3 was applied, apoptosis was induced, as determined by an immunohistochemical staining of fragmented genome DNA and cell profiles. Significant inhibition of Bcl-2 oncogene protein expression by the same concentration of FNQ3 also was demonstrated by an immunohistochemical staining method to visualize the expressed cells and Western blot in polyacrylamide gel electrophoresis. Flow-cytometric spectra showed S-phase arrest in cell cycles and the appearance of sub-G1 phase consistent with apoptosis. On the other hand, concentrations of 5 microg/ml or more of FNQ3 induced necrosis. These results show that FNQ3 may act as an antitumor agent to induce apoptosis by affecting Bcl-2 expression and cell cycles, or necrosis as the result of primary mitochondrial injuries.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Cell Cycle; Cervix Uteri; DNA; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Epithelial Cells; Female; Flow Cytometry; HeLa Cells; Humans; Immunohistochemistry; Mitochondria; Naphthoquinones; Necrosis; Proto-Oncogene Proteins c-bcl-2; S Phase; Time Factors; Uterine Cervical Neoplasms

The effect of the novel anticancer 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) on human osteosarcoma cell lines (HuO9 and HuO9N2) was investigated. The IC50 values of FNQ3 were 5.95 microM for HuO9 and 3.86 microM for HuO9N2, while that for normal fibroblasts (WI-38 cell line) was 35.8 microM. The selectivity in antitumour activity which was estimated from the IC50 ratio of normal fibroblasts to tumour cells was 6.0 and 9.3 fold for HuO9 and HuO9N2, respectively. FNQ3 at 23.6 microM selectively injured mitochondria of HuO9 cells starting at 36 h and HuO9N2 cells at 24 h, whereas WI-38 cells were unaffected even after 72 h. These results demonstrated that FNQ3 was selectively toxic to the mitochondria of osteosarcoma cells similar to carcinoma cells (Pan et al. (1997) J. Electron Microsc. 46: 181), in comparison to normal cells.

Topics: Antineoplastic Agents, Phytogenic; Cell Division; Cell Line; Fibroblasts; Humans; Mitochondria; Naphthoquinones; Osteosarcoma; Tumor Cells, Cultured

Japanese encephalitis still occurs in endemic and epidemic forms over a wide area of Asia. Although the vaccine against Japanese encephalitis virus (JEV) is widely used, no antiviral drug has been reported. We used several different kinds of furanonaphthoquinone derivatives and found antiviral activity against JEV. Especially, 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) indicated the highest antiviral activity, followed by 2-(1-hydroxyethyl)-, 5(or 8)-hydroxy-, and 2-methyl-5(or 8)-hydroxy-analogs of naphtho[2,3-b]furan-4,9-dione. In the presence of 3 microg/ml FNQ3, the virus yields in Vero cells were 2 x 10(5) PFU/ml at 24 h after infecting with the virus and 10% of the control level. Western blot analysis using anti-E rabbit sera or anti-NS3 showed that the expression of viral proteins was inhibited by treatment with FNQ3. In addition, Northern blot analysis indicated that the appearance of JEV-RNA was also inhibited by FNQ3. These results suggest that FNQ3 inhibits JEV replication through viral RNA and protein synthesis.

Topics: Animals; Antiviral Agents; Blotting, Northern; Blotting, Western; Chlorocebus aethiops; Cytopathogenic Effect, Viral; Encephalitis Virus, Japanese; Membrane Glycoproteins; Naphthoquinones; RNA Helicases; RNA, Viral; Serine Endopeptidases; Vero Cells; Viral Envelope Proteins; Viral Nonstructural Proteins; Viral Plaque Assay; Virus Replication

Analogs of furanonaphthoquinone (FNQ) from Tecoma ipe Mart had MICs ranging from 1.56 to 25 microg/ml against gram-positive bacteria. FNQ showed significantly lower MICs against methicillin-resistant Staphylococcus aureus than against methicillin-sensitive S. aureus. FNQ inhibited Helicobacter pylori with an MIC of 0.1 microg/ml. Fungi, including pathogenic species, were sensitive to FNQ with MICs similar to those of amphotericin B.

Topics: Aspergillus; Candida; Gram-Positive Bacteria; Methicillin Resistance; Microbial Sensitivity Tests; Naphthoquinones; Staphylococcus aureus

The intracellular ultrastructural changes induced by the new antitumour agent 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) were investigated in human cervical cancer HeLa cells in comparison with normal cervix cells. The normal cells were isolated from cervixes surgically resected from myoma patients and were keratin positive. FNQ3 at 3-5 micrograms ml-1 selectively damaged the HeLa cell mitochondria followed by rough-surfaced endoplasmic reticulum resulting in cell death. In contrast, normal cells remained unaffected at that concentration but were damaged by 20 micrograms ml-1 FNQ3. The FNQ3-induced tumour cell toxicity was inhibited 52% and 36% by trolox and a water-soluble fraction of the antioxidative substance AOB, respectively. The results indicated that FNQ3 is selectively toxic to HeLa cells at approximately eight times that of normal cells in terms of mitochondrial alteration and free radical formation.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Cell Survival; Cells, Cultured; Cervix Uteri; Chromans; Epithelial Cells; Epithelium; Female; Free Radical Scavengers; HeLa Cells; Humans; Keratins; Mitochondria; Naphthoquinones