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Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?

100%

Nawrot B.

Acta Biochimica Polonica

2004

tom 51

nr 2

ß-Secretase, a ß-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of ß-amyloid peptides (Aß), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Aß is the primary influence driving AD pathogenesis. Lowering of Aß secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, ß-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human ß-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids — ribozymes and deoxyribozymes — as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with S-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Aß40 and Aß42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer’s disease and for future drug design.

DNAzyme as an efficient tool to modulate invasiveness of human carcinoma cells

67%

Wiktorska M., Papiewska-Pajak I., Okruszek A., Sacewicz-Hofman I., Niewiarowska J.

Acta Biochimica Polonica

2010

tom 57

nr 3

In this study we evaluated efficiency of DNAzymes to modulate motility of cancer cells, an important factor in the progression and metastasis of cancers. For this purpose we targeted β1 integrins that are predominant adhesive receptors in various carcinoma cell lines (CX1.1, HT29, LOVO, LS180, PC-3). To evaluate invasiveness of cancer cells, we used a transwell migration assay that allowed analyzing chemotactic migration of colon carcinoma cell lines across an ECM-coated membrane. Their adhesive properties were also characterized by the analysis of adhesion to fibronectin, laminin and collagen. In addition, the expression of major integrin subunits, selected intact β1 integrins, and other adhesive receptors (ICAM, E-selectin, uPAR) was analyzed by flow cytometry. Inhibition of β1 integrin expression by DNAzyme to β1 mRNA almost abolished the invasiveness of the CX1.1, HT29, LS180, LOVO and PC-3 cells in vitro. These data show that DNAzymes to β1 integrin subunit can be used to inhibit invasiveness of carcinoma cells.

Ograniczanie wyników

2 Acta Biochimica Polonica

1 Nawrot B.

1 Niewiarowska J.

1 Okruszek A.

1 Papiewska-Pajak I.

1 Sacewicz-Hofman I.

1 Wiktorska M.

1 2010

1 2004

Wyniki wyszukiwania

Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?

DNAzyme as an efficient tool to modulate invasiveness of human carcinoma cells