griseofulvin and Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Microtubules, composed of alphabeta tubulin dimers, are dynamic polymers of eukaryotic cells. They play important roles in various cellular functions including mitosis. Microtubules exhibit differential dynamic behaviors during different phases of the cell cycle. Inhibition of the microtubule assembly dynamics causes cell cycle arrest leading to apoptosis; thus, qualifying them as important drug targets for treating several diseases including cancer, neuronal, fungal, and parasitic diseases. Although several microtubule-targeted drugs are successfully being used in cancer chemotherapy, the development of resistance against these drugs and their inherent toxicities warrant the development of new agents with improved efficacy. Several antimicrotubule agents are currently being evaluated for their possible uses in cancer chemotherapy. Benomyl, griseofulvin, and sulfonamides have been used as antifungal and antibacterial drugs. Recent reports have shown that these drugs have potent antitumor potential. These agents are shown to inhibit proliferation of different types of tumor cells and induce apoptosis by targeting microtubule assembly dynamics. However, unlike vincas and taxanes, which inhibit cancer cell proliferation in nanomolar concentration range, these agents act in micromolar range and are considered to have limited toxicities. Here, we suggest that these drugs may have a significant use in cancer chemotherapy when used in combination with other anticancer drugs.

Topics: Animals; Antineoplastic Agents; Benomyl; Griseofulvin; Humans; Microtubules; Mitosis; Models, Biological; Models, Molecular; Neoplasms; Paclitaxel; Protein Conformation; Sulfonamides; Tubulin; Vinblastine

Griseofulvin (GF) has been in use for more than 30 years as a pharmaceutical drug in humans for the treatment of dermatomycoses. Animal studies give clear evidence that it causes a variety of acute and chronic toxic effects, including liver and thyroid cancer in rodents, abnormal germ cell maturation, teratogenicity, and embroyotoxicity in various species. No sufficient data from human studies are available at present to exclude a risk in humans: therefore, attempts were made to elucidate the mechanisms responsible for the toxic effects of GF and to address the question whether such effects might occur in humans undergoing GF therapy. It is well documented that GF acts as a spindle poison and its reproductive toxicity as well as the induction of numerical chromosome aberrations and of micronuclei in somatic cells possibly may result from disturbance of microtubuli formation. Likewise, a causal relationship between aneuploidy and cancer has been repeatedly postulated. However, a critical survey of the data available on aneuploidogenic chemicals revealed insufficient evidence for such an association. Conceivably, other mechanisms may be responsible for the carcinogenic effects of the drug. The induction of thyroid tumors in rats by GF is apparently a consequence of the decrease of thyroxin levels and it is unlikely that such effects occur in GF-exposed humans. The appearance of hepatocellular carcinomas (HCC) in mice on GF-supplemented diet is preceded by various biochemical and morphological changes in the liver. Among these, hepatic porphyria is prominent, it may result from inhibition of ferrochelatase and (compensatory) induction of ALA synthetase. GF-induced accumulation of porphyrins in mouse liver is followed by cell damage and necrotic and inflammatory processes. Similar changes are known from certain human porphyrias which are also associated with an increased risk for HCC. However, the porphyrogenic effect of GF therapy in humans is moderate compared with that in the mouse model, although more detailed studies should be performed in order to clarify this relationship on a quantitative basis. A further important effect of GF-feeding in mice is the formation of Mallory bodies (MBs) in hepatocytes. These cytoskeletal abnormalities occur also in humans, although under different conditions; their appearance is associated with the induction of liver disease and HCC. Chronic liver damage associated with porphyria and MB formation, enhanced cell prolifera

Topics: Aneuploidy; Animals; Antifungal Agents; Carcinogenicity Tests; Cell Transformation, Neoplastic; Griseofulvin; Humans; In Vitro Techniques; Liver; Mice; Mutagenicity Tests; Neoplasms; Rats; Reproduction; Risk Assessment; Tissue Distribution

In the biosynthetic study of griseofulvin by Penicillium urticae and microbial transformation of (-)- and (+)-dehydrogriseofulvin and their derivatives by Streptomyces cinereocrocatus excellent informations were obtained from 2H-NMR spectroscopy. In the reduction of (-)-dehydrogriseofulvin into (+)-griseofulvin by a partially purified enzyme system of S. cinereocrocatus, the origin of the 6' alpha-hydrogen of (+)-griseofulvin was a hydride ion donated by pro-4R-hydrogen of NADPH. In connection with the study of carcinogenesis, diethylstilbestrol (DES) was proved to disrupt microtubules in vitro. The other synthetic estrogens, E,E-dienestrol, meso-hexestrol, and dl-hexestrol were inhibitors of microtubule assembly in vitro, and induced twisted ribbon structures or ribbon-sheet-microtubules from microtubule proteins. Next, the effects of DES and its methyl ethers on the chromosome of and the cellular microtubule architecture, revealed by fluorescent anti-tubulin antibody, of Chinese hamster V79 cells were examined, and further estradiol-17 beta was proved to exhibit higher microtubule-disruptive activity than DES in V79 cells. Furthermore, cytoplasmic microtubules in the human breast cancer cell lines MCF-7 and MDA-MB-231, estrogen receptor-positive and -negative cell lines, respectively, were disrupted equally by estradiol-17 beta. Then, natural estrogens and their derivatives comprising 30 compounds in total were tested in Chinese hamster V79 cells, proving that 2-methoxyestradiol showed the strongest activity (EC50: 2 microM) to disrupt microtubules. Further, in the assay of indenestrol A, a metabolite of DES, indenestrol B and their monomethyl ethers, the 4'-methyl ether of [(-)-3S]-indenestrol B exhibited both the strongest cytotoxicity in, and greatest disruption of the cellular microtubules of V79 cells, and no correlation with the affinity for estrogen receptors was shown.

Topics: 2-Methoxyestradiol; Animals; Cricetinae; Estradiol; Estrogens; Female; Griseofulvin; Humans; Microtubule Proteins; Microtubules; Neoplasms; Penicillium; Streptomyces

Humans are susceptible to the carcinogenic action of a small group of organic and inorganic chemicals in certain industrial, medical, and social habit exposures. A larger number and wider variety of chemical carcinogens, primarily organic compounds, are known for experimental animals. Chemical carcinogens are also found among the metabolites of living cells. No common structure is evident among chemical carcinogens, and a majority of these agents are precarcinogens that require metabolic activation into reactive electrophilic ultimate carcinogens. These strong electrophiles combine covalently with nucleophilic sites in DNAs, RNAs, and proteins in target tissues. One or more of these adducts appear to initiate carcinogenesis. About 20 naturally occurring organic chemical carcinogens, primarily metabolites of green plants and fungi, are known; some occur in some human foods. Many other naturally chemical carcingens doubtless exist among the vast number of uncharacterized nonnutritive minor components of living systems, some of which are sources of human foods. The electrophilic forms of chemical carcinogens are mutagenic, and mammalian tissue-mediated mutagenicity assays appear promising in the detection of potential chemical carcinogens. These assays should serve at least as a prescreen for conventional lifetime tests in rodents for the carcinogenic activity of food components and contaminants. Epidemiological approaches appear necessary to evaluate the importance of the naturally occurring chemical carcinogens in the occurrence of human cancer.

Topics: Aflatoxins; Animals; Carcinogens, Environmental; Cycasin; Ethionine; Food; Griseofulvin; Humans; Neoplasms; Nitrosamines; Plants; Pyrrolizidine Alkaloids; Safrole; Sterigmatocystin; Streptomyces; Toxins, Biological

Topics: Aflatoxins; Animals; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cell Transformation, Neoplastic; Cricetinae; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Environmental Exposure; Europe; Griseofulvin; Hydrocarbons; Japan; Male; Methylcholanthrene; Mice; Microsomes, Liver; Mitomycins; Neoplasms; Nitrosoguanidines; Plant Extracts; Prostate; Rats; United States

Topics: Alkylating Agents; Animals; Anthelmintics; Carcinogens; Environmental Exposure; Griseofulvin; Humans; Iron-Dextran Complex; Isoniazid; Mice; Mustard Compounds; Neoplasms; Neoplasms, Experimental; Occupational Diseases; Urinary Bladder Neoplasms

Topics: Alkaloids; Amides; Animals; Antineoplastic Agents; Asparaginase; Cell Division; Colchicine; Cytarabine; DNA; Griseofulvin; Humans; Hydroxyurea; Mice; Neoplasms; Nucleosides; Thiosemicarbazones; Vinblastine; Vincristine

Topics: Aluminum; Arsenic; Aspergillus; Beryllium; Carcinogens; Carrageenan; Citrus; Croton Oil; Food Contamination; Fruit; Griseofulvin; Herbicides; Humans; Hydrazines; Insecticides; Iron; Metals; Neoplasms; Neoplasms, Experimental; Penicillium; Plants, Edible; Polysaccharides; Rats; Research; Senecio; Tannins; Thiourea

Griseofulvin, an antifungal drug, has been shown in recent years to have anti-proliferative activities. We report here the synthesis of new analogs of griseofulvin, substituted in 2' by a sulfonyl group or in 3' by a sulfinyl or sulfonyl group. These compounds exhibit good anti-proliferative activities against SCC114 cells, an oral squamous carcinoma cell line showing pronounced centrosome amplification, and unexpected cytotoxic activities on HCC1937 cells, a triple negative breast cancer cell line resistant to microtubule inhibitors.

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Griseofulvin; Humans; Neoplasms; Sulfones; Sulfoxides

Griseofulvin was identified as an inhibitor of centrosomal clustering in a recently developed assay. Centrosomal clustering is an important cellular event that enables bipolar mitosis for cancer cell lines harboring supernumerary centrosomes. We report herein the synthesis and SAR of 34 griseofulvin analogues as inhibitors of centrosomal clustering. The variations in the griseofulvin structure cover five positions, namely the 4, 5, 2', 3', and 4' positions. Modification of the 4 and 5 positions affords inactive molecules. The enol ether must be at the 2' position, and the 4' position needs to be sp(2) hybridized. The most active analogues were the 2'-benzyloxy and 2'-(4-methylbenzyloxy) analogues as well as the oxime of the former with a 25-fold increase of activity compared to griseofulvin. Comparison of the results obtained in this work with prior reported growth inhibition data for dermatophytic fungi showed both similarities and differences.

Topics: Antifungal Agents; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Centrosome; Griseofulvin; Humans; Mitosis; Neoplasms; Oximes; Structure-Activity Relationship

Topics: Animals; Antifungal Agents; Apoptosis; Cell Line, Tumor; Centrosome; Griseofulvin; Humans; Mitosis; Neoplasms; Spindle Apparatus

Topics: Analgesics; Anesthetics; Animals; Antineoplastic Agents; Arsenic; Griseofulvin; Histamine H1 Antagonists; Hormones; Humans; Hypnotics and Sedatives; Isoniazid; Neoplasm Transplantation; Neoplasms; Nitroso Compounds; Secologanin Tryptamine Alkaloids; Sweetening Agents; Tannins

Topics: Animals; Arsenic; Carcinogens; Estrogens; Griseofulvin; Humans; Hypoglycemic Agents; Isoniazid; Mice; Neoplasms; Nitrogen Mustard Compounds; Radiography; Radiotherapy; Rats; Sulfonamides; Thorium Dioxide; Trypan Blue; Urethane

Topics: Dermatomycoses; Griseofulvin; Mycoses; Neoplasms; Recurrence

Topics: Alloxan; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antibody Formation; Antineoplastic Agents; Benzimidazoles; Borates; Caffeine; Cyanides; Dermatologic Agents; Fluoroacetates; Glucosamine; Griseofulvin; Neoplasms; Nitrites; Pyridoxine

Topics: Cell Division; Griseofulvin; HeLa Cells; Humans; Mitosis; Neoplasms

Topics: Griseofulvin; Mycoses; Neoplasms; Recurrence

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Griseofulvin; Methylcholanthrene; Mice; Neoplasms; Neoplasms, Experimental

Topics: Griseofulvin; Humans; Neoplasms; Recurrence; Tinea; Trichophyton