Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several polycations such as polylysine polymers are efficient transfection agents due to their capacity to bind DNA at physiological pH. By linking a ligand for a cell surface receptor to the polycation domain, a selective delivery of polyanionic compounds such as oligodeoxynucleotides (ODNs) without cell membrane-disruption can be achieved. Therefore, we aimed to develop this strategy to improve the uptake of oligomers in cancer cells. In particular, cationic polymers polylysine were covalently linked to a molecule of Folic Acid (FA) to deliver complexed ODNs in human melanoma (M-14) cells which express FA receptors. Since in these cells c-myc oncogene seems to play a crucial role in tumor growth, we used a c-myc antisense ODNs (15mer base antisense c-myc ODNs phosphorothioate) to inhibit its expression. The cellular uptake of the complexed ODNs was improved compared to the cellular uptake of free ODNs with a significant decrease in the intracellular c-myc protein level, resulting in a reduction of the growth rate and colony-forming capacity of the cells. No such effect was observed when ODNs in scrambled sequences were administered under the same experimental conditions. The efficacy of the uptake of the complex is receptor-related since a Transferrin-polylysine carrier produced no significant biological effects (in melanoma cells the Fe uptake is mediated by an oxidoreductase present in the cell membrane and not by Transferrin receptor pathway). Our results demonstrate that: a) By choosing the appropriate ligand for the membrane receptor present on the target cells, selective targeting of ODNs can be achieved. b) The uptake of the ODNs can be improved by receptor-mediated endocytosis. c) In a model system the complexed ODNs are capable of impairing gene product synthesis and function.
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PMID:Folic acid-polylysine carrier improves efficacy of c-myc antisense oligodeoxynucleotides on human melanoma (M14) cells. 906 27

Methionine dependency of tumor growth, although not well-understood, is detectable by 11C-methionine positron emission tomography and may contribute to the aggressivity of glioblastomas (GBM) and meningiomas. Cytosolic folate cycle is required for methionine synthesis. Its dysregulation may influence cell reprogramming towards pluripotency. We evaluated methionine-dependent growth of monolayer (ML) cells and stem cell-like tumor spheres (TS) derived from 4 GBM (U251, U87, LN299, T98G) and 1 meningioma (IOMM-LEE) cell lines. Our data showed that for all cell lines studied, exogenous methionine is required for TS formation but not for ML cells proliferation. Furthermore, for GBM cell lines, regardless of the addition of folate cycle substrates (folic acid and formate), the level of 3 folate isoforms, 5-methytetrahydrofolate, 5,10-methenyltetrahydrofolate, and 10-formyltetrahydrofolate, were all downregulated in TS relative to ML cells. Unlike GBM cell lines, in IOMM-LEE cells, 5-methyltetrahydrofolate was actually more elevated in TS than ML, and only 5,10-methenyltetrahydrofolate and 10-formyltetrahydrofolate were downregulated. The functional significance of this variation in folate cycle repression was revealed by the finding that Folic Acid and 5-methyltetrahydrofolate promote the growth of U251 TS but not IOMM-LEE TS. Transcriptome-wide sequencing of U251 cells revealed that DHFR, SHMT1, and MTHFD1 were downregulated in TS vs ML, in concordance with the low activity cytosolic folate cycle observed in U251 TS. In conclusion, we found that a repressed cytosolic folate cycle underlies the methionine dependency of GBM and meningioma cell lines and that 5-methyltetrahydrofolate is a key metabolic switch for glioblastoma TS formation. The finding that folic acid facilitates TS formation, although requiring further validation in diseased human tissues, incites to investigate whether excessive folate intake could promote cancer stem cells formation in GBM patients.
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PMID:Folate can promote the methionine-dependent reprogramming of glioblastoma cells towards pluripotency. 3139 52