thiouracil 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

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Azaguanine; Azaserine; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Floxuridine; Fluorouracil; Folic Acid; Glutamine; Leukemia L1210; Mercaptopurine; Methotrexate; Mitomycin; Neoplasms; Neoplasms, Experimental; Pharmacology; Purines; Puromycin; Pyrimidines; Research; RNA; RNA, Neoplasm; Thioguanine; Thiouracil

A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Blood-Brain Barrier; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Drug Design; Drug Resistance, Neoplasm; HCT116 Cells; Humans; K562 Cells; MCF-7 Cells; Mice; Mice, Nude; Microtubules; Neoplasms; Polymerization; Sulfonamides; Tubulin; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Abdominal Neoplasms; Animals; Castration; Female; Heart Neoplasms; Hypoxia; Injections, Intraperitoneal; Injections, Intravenous; Intestinal Neoplasms; Kidney Neoplasms; Male; Mammary Neoplasms, Experimental; Neoplasms; Neoplasms, Experimental; Nitroso Compounds; Nitrosourea Compounds; Rats; Rats, Inbred Strains; Stomach Neoplasms; Testosterone; Thiouracil; Tongue Neoplasms; Urea

Topics: Aminohydrolases; Animals; Annelida; Carcinoma, Hepatocellular; Escherichia coli; Liver Neoplasms; Male; Mice; Neoplasms; Nucleotidases; Prostate; Rats; Ribonucleases; RNA, Transfer; Species Specificity; Thiouracil

Topics: Animals, Newborn; Chromatography; Iodine Isotopes; Neoplasm Transplantation; Neoplasms; Pathology; Rats; Research; Thiouracil; Thymectomy; Thyroid Hormones; Thyroid Neoplasms; Thyroxine; Toxicology; Triiodothyronine

Topics: Carcinoma; Endometriosis; Endometritis; Female; Goiter; Graves Disease; Humans; Hyperthyroidism; Iodine Isotopes; Myxedema; Neoplasms; Ovarian Neoplasms; Salpingitis; Thiouracil; Thyroid Diseases; Thyroidectomy; Tuberculosis; Tuberculosis, Female Genital; Uterine Cervical Neoplasms; Uterine Neoplasms

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Blood; Body Weight; Estradiol; Growth Hormone; Hydrocortisone; Neoplasms; Neoplasms, Experimental; Pharmacology; Pituitary Neoplasms; Prolactin; Rats; Research; Thiouracil; Thymus Gland; Thyroxine

Topics: Animals; Neoplasms; Neoplasms, Experimental; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Carcinogenesis; Diet; Neoplasms; Pituitary Gland; Pituitary Gland, Anterior; Pituitary Neoplasms; Rats; Thiouracil; Thyroid Gland; Thyrotrophs

Topics: Animals; Hepatomegaly; Liver; Neoplasms; Neoplasms, Experimental; Rats; Thiouracil

Topics: Antineoplastic Agents; Humans; Neoplasms; Thiouracil

Topics: Animals; Carbon Tetrachloride; Female; Humans; Leadership; Neoplasms; Neoplasms, Experimental; Ovary; Rats; Thiouracil; Transplants

Topics: Animals; Fluorenes; Methylthiouracil; Neoplasms; Neoplasms, Experimental; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Methylthiouracil; Neoplasms; Neoplasms, Experimental; Rats; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Mice; Neoplasms; Neoplasms, Experimental; Pituitary Gland; Pituitary Neoplasms; Thiouracil; Thyroid Gland

Topics: Neoplasms; Thiouracil; Thyroid Gland; Thyroid Neoplasms; Viscera

Topics: Acetylcholine; Animals; Cholinergic Agents; Cholinesterase Inhibitors; Female; Goiter; Hyperplasia; Neoplasms; Neostigmine; Pregnancy; Pregnancy Complications; Rats; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Hyperthyroidism; Methylthiouracil; Neoplasms; Thiazoles; Thiouracil

Topics: Adenoma; Humans; Neoplasms; Pregnancy; Thiouracil; Thyroid Gland; Viscera

Topics: Animals; Estrogens; Neoplasms; Neoplasms, Experimental; Pituitary Gland; Pituitary Neoplasms; Rats; Thiouracil; Thiourea; Thyroid Gland; Thyroxine

Topics: Animals; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Physiological Phenomena; Thiouracil; Thyroid Gland

Topics: Animals; Catalase; Liver; Neoplasms; Oxidation-Reduction; Thiouracil; Thyroid Gland; Thyroidectomy

Topics: Graves Disease; Humans; Hyperthyroidism; Neoplasms; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Iodine; Iodine Radioisotopes; Neoplasms; Radioisotopes; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Iodides; Neoplasms; Pituitary Diseases; Pituitary Gland; Propylthiouracil; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Carcinogens; Mice; Neoplasms; Pituitary Gland; Pituitary Gland, Anterior; Pituitary Neoplasms; Thiouracil

Topics: Animals; Iodine; Iodine Radioisotopes; Methylthiouracil; Neoplasms; Neoplasms, Experimental; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Aging; Animals; Carcinogenesis; Cell Transformation, Neoplastic; Neoplasms; Rats; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Mice; Neoplasms; Neoplasms, Experimental; Pituitary Gland; Pituitary Neoplasms; Propylthiouracil; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Eating; Mice; Neoplasms; Thiouracil

Topics: Animals; Biological Phenomena; Mice; Neoplasms; Physiological Phenomena; Thiouracil; Thyroid Gland

Topics: Carcinogenesis; Humans; Liver Neoplasms; Neoplasms; Thiouracil; Uracil

Topics: Carcinoma; Iodine; Iodine Radioisotopes; Neoplasms; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Endocrine System Diseases; Mice; Neoplasms; Nutritional Physiological Phenomena; Nutritional Sciences; Nutritional Status; Thiouracil; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Breast Neoplasms; Female; Humans; Mice; Mice, Inbred C3H; Neoplasms; Thiouracil

Topics: Acetamides; Animals; Methylthiouracil; Neoplasms; Rats; Thiouracil; Thyroid Gland; Thyroxine

Topics: Carcinoma; Humans; Neoplasms; Thiouracil

Topics: Hyperthyroidism; Neoplasms; Thiouracil; Thyroid Gland; Thyrotoxicosis

Topics: Adrenal Gland Neoplasms; Adrenal Glands; Blood Pressure; Humans; Hypertension; Methylthiouracil; Neoplasms; Pheochromocytoma; Thiouracil

Topics: Adenoma; Adult; Humans; Hyperthyroidism; Neoplasms; Thiouracil; Thyroid Gland; Thyroid Neoplasms; Thyrotoxicosis

Topics: Goiter; Hypertrophy; Neoplasms; Thiouracil; Thyroid Gland; Thyrotoxicosis