Background: Unpredictable clinical behavior of glioblastoma multiforme suggests distinct molecular subtypes. Results: Metabolic profiles of different glioblastoma lines indicate distinct subtypes correlated with gene expression differences. Conclusion: A subset of metabolites can be used to distinguish between four subtypes of glioblastomas. Significance: Metabolic profiling of cancers provides a way for subtype determination with possible diagnostic and prognostic applications.
A series of PF-8380 analogs, a recently developed autotaxin inhibitor, was explored. Inhibition of autotaxin by these analogs, as well as by all PF-8380 synthetic intermediates, shows the importance of meta-dichlorobenzyl and benzo[d]oxazol-2(3H)-one fragments. However, analogs 8 and 9, bearing only the benzo[d]oxazol-2(3H)-one moiety, are more cytotoxic on the LN229 glioblastoma cell line than PF-8380 and temozolomide (TMZ).
Changes across metabolic networks are emerging as an integral part of cancer development and progression. Increasing comprehension of the importance of metabolic processes as well as metabolites in cancer is stimulating exploration of novel, targeted treatment options. Arachidonic acid (AA) is a major component of phospholipids. Through the cascade catalyzed by cyclooxygenases and lipoxygenases, AA is also a precursor to cellular signaling molecules as well as molecules associated with a variety of diseases including cancer. 5-Lipoxygenase catalyzes the transformation of AA into leukotrienes (LT), important mediators of inflammation. High-throughput analysis of metabolic profiles was used to investigate the response of glioblastoma cell lines to treatment with 5-lipoxygenase inhibitors. Metabolic profiling of cells following drug treatment provides valuable information about the response and metabolic alterations induced by the drug action and give an indication of both on-target and off-target effects of drugs. Four different 5-lipoxygenase inhibitors and antioxidants were tested including zileuton, caffeic acid, and its analogues caffeic acid phenethyl ester and caffeic acid cyclohexethyl ester. A NMR approach identified metabolic signatures resulting from application of these compounds to glioblastoma cell lines, and metabolic data were used to develop a better understanding of the mode of action of these inhibitors.
The inhibition of protein synthesis by actinomycin D can be prevented or reversed by selected aromatic compounds. Durham & Keudell (1969) reported that Pseudomonas fluorescens NND produced an inducible enzyme, protocatechuate oxidoreductase (EC 1.13.1.3), in the presence of the antibiotic. The inducer, protocatechuate, prevented and reversed the inhibition by actinomycin D of growth and macromolecular syntheses in a synthetic succinate-salts medium. It has also been established that protocatechuate prevented or reversed the inhibition by actinomycin D of synthesis of an acyltransferase (amidase; acylamide aminohydrolase, EC 3.5.1.4) in this organism (Ferguson & Durham, 1970). Actinomycin D has been reported to inhibit by binding to the guanine moiety of double-stranded helical DNA (Cerami, Reich, Ward & Goldberg, 1967), although the presence of guanine may not be a sufficient requisite (Wells, 1969; Hyman & Davidson, 1971). The prevention and reversal studies with protocatechuate emphasize the unique ability of microbial cells to grow or synthesize proteins in the presence of a DNA-binding component. Alleviation of the inhibition suggests that complexing of the antibiotic with cellular DNA is a reversible process, and it has been proposed that protocatechuate (3,4-dihydroxybenzoate) interacts with actinomycin D to negate the antimicrobial action (Durham & Keudell, 1969). The present study establishes that selected aromatic compounds demonstrate the potential for reversal and that the specificity of the molecule is very important in determining the ability of the compound to complex or interact with the antibiotic. Growth and enzyme-induction studies with P.
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