Cell proliferation, biotin

Although a number of cell lines were shown to be sensitive to inhibition by PatA (Low et al., 2005), we selected RKO cells (IC50 of 0.4 nM in cell proliferation assay) to prepare lysates for the isolation and identification of target protein(s). We often select RKO cells for target identification of small molecules using biotin-conjugates, because they appear to be particularly suitable for target protein isolation. 

Biotin is essential for cell proliferation. Peripheral blood mononuclear cells appear to take up biotin by a system that is distinct from the sodium-dependent multivitamin transporter that is responsible for intestinal and renal uptake of biotin (Section 11.1). In response to mitogenic stimuli the uptake of biotin increases several-fold, with no change in the activity of the sodium-dependent transporter. At the same time, there is an increase in the rate of expression of methylcrotonyl CoA, propionyl CoA carboxylases, and holocarboxylase... 

The transcriptional factor NF-kB is a protein complex that controls the transcription of DNA. NF-kB is found in almost all animal cell types and is involved in cellular responses to different stimuli, e.g. stress, cytokines, free radicals, ultraviolet irradiation, oxidized low density lipoprotein (LDL) and bacterial or viral antigens. NF-kB plays a key role in regulating the immune response to infection and is widely used by eukaryotic cells as a regulator of genes that controls cell proliferation and cell survival. Biotin deficiency is associated with increased nuclear translocation of NF-kB, enhancing the transcriptional activity of antiapoptotic genes in human lymphoid cells (Rodriguez-Melendez et al. 2004). 

CRISP, S. E. R. H., CAMPGREALE, G., WHITE, B. R., TGGMBS, C. F., GRIFEIN, J. B., SAID, H. M., ZEMPLENI, J. (2004) Biotin supply affects rates of cell proliferation, biotinylation of carboxylases and histones, and expression of the gene encoding the sodium-dependent multivitamin transporter in JAr choriocarcinoma cells. Eur. J. Nutr., 43, 23-31. 

FIGURE 8.5 Proapoprotic experimental therapies in pulmonary arterial hypertension (PAH). A common denominator of these therapies is the induction of apoptosis as well as suppression of proliferation in the pulmonary artery wall. On the left are untreated rats with monocrotaline-induced PAH and on the right are rats treated with elastase inhibitors. Increased apoptosis of the intima-media is showed by TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling), and decreased proliferation is imaged by staining for proliferation cell nuclear antigen (PCNA). The same pattern has been shown in the media of treated rats by all the therapies shown in the box. (From Ref. 116, with permission.)... 

Takeuehi et al. have synthesized biotin-labeled fostriecin (241), which possessed an inhibitory activity against the proliferation of mouse leukemia cells and demonstrated that the fostriecin covalently bound to the Cys269 residue of PP2Ac in HeLa S3 cells. ... 

Vitamins are essential lead compounds for the development of novel radiopharmaceuticals. Many vitamin receptors such as the folate receptor are overexpressed on different tumor cell lines (Parker et al. 2005). Biotin labeled with Tc is under investigation since many years in different settings. A vitamin that has not found as much interest as hiotin is vitamin B12. Since it is a relatively large molecule, it has heen proposed to use B12 as a Trojan horse since rapidly proliferating cells and some bacterial stems show a high demand for this growth essential vitamin. While research toward labeled folate and B12 has intensified over the past couple of years, research with biotin rather slowed down. The biochemical pathways of folate and B12 are interlinked since folate delivers the -CH3 group to the apoenzyme in order to activate it toward its function in the methionine synthase cycle. 

ZEMPLENI, J., HELM, R. M., MOCK, D. M. (2001) in vivo biotin supplementation at a pharmacologic dose decreases proliferation rates of human peripheral blood mononuclear cells and cytokine release. J. Nutr., 131, 1479-1484. 

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