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In seven out of eight human bladder cell lines that were examined herein, growth was more dependent on the presence in the incubation medium of glucose rather than glutamine. The exception was the slowly growing RT4 cells that were more glutamine-dependent. Growth of all the cell lines was reduced by an inhibitor of 6-phosphofructo-2-kinase/2,6-bisphosphatase 3, namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). Growth was also reduced by three compounds that reduce the conversion of glucose to lactate: namely 2-deoxyglucose, butyrate and dichloroacetate. Additive effects were seen when these molecules were combined with 3PO. Treatment of bladder cancer cells with phenformin resulted in growth inhibition that was frequently accompanied by increased glucose uptake and acidification of the medium that was blocked by co-incubation with 3PO. The actions of 3PO suggest that inhibitors of PFKB3 merit further investigation in the treatment of bladder cancer and they may be useful agents in combination with other drugs that inhibit cancer cell proliferation., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

In previous studies performed by our group, we observed that 2-deoxyglucose blocked the acidification of the medium used for culture of colon cancer cells caused by incubation with biguanides and it had an additive inhibitory effect on growth. In the present work, we found that 3-bromopyruvate can also prevent the lowering of pH caused by biguanide treatment. 3-Bromopyruvate inhibited colonic cancer cell proliferation, but the effect was not always additive to that of biguanides and an additive effect was more notable in combined treatment with 3-bromopyruvate and 2-deoxyglucose. The induction of alkaline phosphatase activity by butyrate was not consistently affected by combination with other agents that modified glucose metabolism. The drug combinations that were examined inhibited proliferation of wild-type and p53-null cells and affected colonic cancer lines with different growth rates.

We observed previously that quercetin can increase the activity of the differentiation markers alkaline phosphatase and dipeptidyl peptidase in Caco-2 colon cancer cells. In the present work, we compared the effects of quercetin on cell proliferation and differentiation with the action of related flavonols and quercetin glycosides. Relative to the action of quercetin, effects on growth and enzyme activities did not always follow parallel trends but quercetin 3-glucoside was notably more potent in both respects while quercetin rutinoside was less active. Of the compounds examined, baicalein and myricetin caused the greatest production of hydrogen peroxide when incubated with the medium. Flavonols can have pro-oxidant effects, but our data suggested that this action was not the sole determinant of growth inhibitory or differentiating effects on Caco-2 cells. Our data indicated that effects of quercetin on colon cancer cell lines can be greatly affected by glycoside modification.

Purpose. A structure-activity study was undertaken to determine the influence of side chain length of phenyl alkanoic acids and the degree of unsaturation of phenyl alkenoic acids on the induction of histone acetylation and inhibition of cancer cell proliferation. Materials and methods. Studies on cell proliferation were performed with DS19 mouse erythroleukemic cells, PC-3 human prostate cancer cells and Caco-2 human colon cancer cells. Actions on histone deacetylase and the induction of histone acetylation were compared for 4-phenylbutyrate and structurally related molecules. Results. Increasing inhibition of cell proliferation by phenyl alkanoic acids together with a decrease in cells in S phase and an increase in apoptotic cells was observed with increased chain length between four and ten carbons. Introduction of double bonds into the side chain was associated with increased growth inhibition. In contrast, 4-phenylbutyrate was a more potent inhibitor of histone deacetylase and inducer of histone acetylation than the other phenyl alkanoic acids examined. Conclusions. In comparison with the action of 4-phenylbutyrate, actions other than inhibition of histone deacetylase appear to be more important for growth inhibition by longer chain phenyl alkanoic and phenyl alkenoic acids. [ABSTRACT FROM AUTHOR]

Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. [ABSTRACT FROM AUTHOR]