captax 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

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

To investigate mortality and cancer morbidity in workers from a factory manufacturing chemicals for the rubber industry.. The mortality (1955-96) and cancer morbidity experience (1971-92) of a cohort of 2160 male production workers from a chemical factory in north Wales were investigated. All subjects had at least 6 months employment at the factory and some employment in the period 1955-84. Detailed job histories were abstracted from company computerised records and estimates of individual cumulative exposure to 2-mercaptobenzothiazole (MBT) and its derivatives were obtained, with a job exposure matrix derived by a former factory hygienist. Durations of employment in the aniline, phenyl-beta-naphthylamine (PBN) and o-toluidine departments were also calculated. Two analytical approaches were used, indirect standardisation and Poisson regression.. Based on serial rates for the general population of England and Wales, observed mortality for the total cohort was close to expectation for all causes (observed (obs) deaths 1131, expected (exp) deaths 1114.5, standardised mortality ratio (SMR) 101), and for all cancers (obs 305, exp 300.2, SMR 102). There was a significant (p < 0.05) excess mortality from cancer of the bladder in the 605 study subjects potentially exposed to one or more of the four chemicals being investigated (obs 9, exp 3.25, SMR 277, 95% confidence interval (95% CI) 127 to 526). This excess was dependent primarily on deaths occurring > 20 years after first exposure in those who started employment before 1955 (obs 7, exp 1.25, SMR 560, 95% CI 225 to 1154, p < 0.001). There were 30 subjects in the total study cohort who, on the basis of death certificates or cancer registration particulars, had had malignant bladder cancer. In separate analyses of the four exposure history variables (after adjustment for age), Poisson regression showed significant positive trends for risk of notification of bladder cancer increasing with cumulative duration of employment in the PBN (p < 0.001) and o-toluidine departments (p < 0.01); similar findings were not obtained for cumulative exposure to MBT or for duration of employment in the aniline department. In a simultaneous analysis of all four chemical exposure variables, a significant positive trend remained for duration of employment with exposure to PBN (p < 0.05). Further analyses of all cases of bladder cancer (malignant and benign diagnoses) used employment histories lagged by 15 years; similar findings were obtained.. It seems likely that some members of this cohort have had occupational bladder cancer. Confident interpretation is difficult because of small numbers in the exposed subcohorts, relatively crude measures of exposure assessment for the four chemicals under study, and presence of unconsidered potential chemical confounders. The simplest interpretation of the findings about bladder cancer may be that PBN (or a chemical reagent or chemical intermediate associated with its production at this factory in the 1930s and 1940s) is a bladder carcinogen. Priority should be given, however, to obtaining information on the cancer experience of other working populations exposed to PBN or to o-toluidine.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Aged, 80 and over; Aniline Compounds; Benzothiazoles; Cohort Studies; Humans; Male; Middle Aged; Neoplasms; Occupational Diseases; Occupational Exposure; Rubber; Thiazoles; Toluidines; Wales

Mortality trends for 1059 production workers at a rubber chemicals plant in Nitro, West Virginia were examined to find whether they had increased mortality from cancer associated with exposure to 2-mercaptobenzothiazole (MBT). This chemical and its derivatives are vulcanising agents that have been manufactured at the plant since 1935. Analyses were conducted on MBT exposed employees by cumulative exposure and time since first exposure, and were also stratified by past assignment to p-aminobiphenyl (PAB) related departments; PAB is a potent bladder carcinogen that was used at the plant between 1935 and 1955. There was an excess of bladder cancer in MBT workers who had PAB related assignments (standardised mortality ratio (SMR) = 3200, 95% confidence interval (95% CI) 1286-6593). In employees without a job assignment with exposure to PAB, there were no associations between exposure to MBT and increased rates of most malignant neoplasms. The SMR for bladder cancer was increased based on three deaths (SMR = 455, 95% CI 94-1328), although these results were too few to evaluate trends by cumulative exposure category. The possibility of confounding by PAB for exposures for jobs that covered all areas of the plant for these three cases must be considered in the light of the potency of PAB as a bladder carcinogen. There were no deaths from bladder cancer among MBT workers hired after the end of manufacture and use of PAB, but the expected number of deaths was only 0.03.

Topics: Adolescent; Adult; Aged; Antimetabolites; Benzothiazoles; Chemical Industry; Cohort Studies; Humans; Male; Middle Aged; Neoplasms; Occupational Diseases; Occupational Exposure; Risk Factors; Thiazoles; West Virginia

Topics: Benzothiazoles; Chemical Industry; Female; Follow-Up Studies; Humans; Male; Neoplasms; Occupational Diseases; Occupational Exposure; Rubber; Sex Factors; Thiazoles; Wales