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Tyrosine kinase, Aurora kinase and leucine aminopeptidase as attractive drug targets in anticancer therapy - characterisation of their inhibitors

100%

Ziemska J., Solecka J.

Roczniki Państwowego Zakładu Higieny

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2016

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tom 67

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nr 4

Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies. These include receptor tyrosine kinases (e.g. EGFR enzymes) and non-receptor tyrosine kinases (Src enzymes), type A, B and C Aurora kinases and aminopeptidases, especially leucine aminopeptidase. We discuss classification of these enzymes, biochemistry as well as their role in the cell cycle under normal conditions and during cancerogenesis. Further on, the work describes enzyme inhibitors that are under in vitro, preclinical, clinical studies as well as drugs available on the market. Both, chemical structures of discovered inhibitors and the role of chemical moieties in novel drug design are discussed. Described enzymes play essential role in cell cycle, especially in mitosis (Aurora kinases), cell differentiation, growth and apoptosis (tyrosine kinases) as well as G1/S transition (leucine aminopeptidase). In cancer cells, they are overexpressed and only their inhibition may stop tumor progression. This review presents the clinical outcomes of selected inhibitors and argues the safety of drug usage in human volunteers. Clinical studies of EGFR and Src kinase inhibitors in different tumors clearly show the need for molecular selection of patients (to those with mutations in genes coding EGFR and Src) to achieve positive clinical response. Current data indicates the great necessity for new anticancer treatment and actions to limit off-target activity.

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Immobilisation of the proteolytic enzyme system [chymotrypsin-exopeptidases] in high-molecular polysaccharides

84%

Idziak J., Moszczynski P.

Polish Journal of Food and Nutrition Sciences

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2000

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tom 09/50

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nr 1

Three kinds of high-molecular polysaccharides: alginate, chitosan and carrageenan, were tested as carriers for the immobilisation of proteolytic enzymes. The catalytic system consisted of the endopeptidase - chymotrypsin and exopeptidases: carboxypeptidase A and leucine aminopeptidase. Subsequently, this immobilised system was used for making of enzymatic hydrolysates of casein. In the case of periodic method of casein hydrolysis the best results (71.9% of tyrosine and tryptophan released) were achieved after 72 h, at substrate concentration 0.5% and with alginate as a carrier. In the semi-continuous method chitosan appeared to be the best carrier and after 72 h the degree of hydrolysis was 48.6% (52.7% of tyrosine and tryptophan released) at the concentration of casein 2%.

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Effects of rearing density on larval growth and activity of digestive enzymes in Lymantria dispar L. [Lepidoptera: Lymantriidae]

84%

Lazarevic J., Peric-Mataruga V., Vlahovic M., Mrdakovic M., Cvetanovic D.

Folia Biologica

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2004

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tom 52

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nr 1-2

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Culturable proteolytic bacteria and the activity of leucine aminopeptidase in river ecosystem

67%

Skorczewski P., Mudryk Z. J.

Polish Journal of Ecology

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2009

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tom 57

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nr 3

561-565

The study determined the numbers and distribution of culturable heterotrophic and proteolytic bacteria and the level of leucine aminopeptidase activity in the water of the Słupia River within the town of Słupsk (Northern Poland). River Słupia is 138.6 km long and flowing into the Baltic Sea. The average water discharge of the river is 15.5 m³ s⁻¹ and its slope is about 1.3% which gives it a mountainous character. The numbers of culturable heterotrophic bacteria was determined on iron-peptone agar (IPA) medium and the numbers of culturable proteolytic bacteria was assayed in IPA medium enriched with gelatin. Potential leucine aminopeptidase activity was carried out with the use of fluorescently labelled model substrate MCA-leucine. The numbers of heterotrophic bacteria ranged between 0.33 to 183.0  10³ cells cm⁻³ (maximum in spring, minimum in winter); the abundance of culturable proteolytic bacteria ranged 0.50 to 31.8  10³ cells cm⁻³ and the maximum was noted in spring, the lowest in summer. The activity of extracellular leucine aminopeptidase ranged from 2.34 to 6.87 μM MCA dm⁻³ h⁻¹ and the highest value was noted in spring while the lowest were noted in winter and summer. The values of bacteriological parameters and of leucine aminopepidase activity tended to be higher below the sewage treatment plant. The bacteriological parameters for River Słupia were compared with the relevant data for other river ecosystems.

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Preliminary evaluation of the isoenzymatic protein variability in selected Poa pratensis L. ecotypes

67%

Slominska-Walkowiak R., Filip E., Szanejko M.

Advances in Agricultural Sciences

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2008

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tom 11

6

Analysis of isozyme polymorphism in dihaploid [DH] lines of triticale [2N-6X-42] X Triticosecale Witt

67%

Slominska-Walkowiak R., Rogalska S. M.

Seria Biologiczna. Uniwersytet im. Adama Mickiewicza w Poznaniu

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2005

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tom 72

7

Cadmium elevates level of protein, amino acids and alters activity of proteolytic enzymes in germinating rice seeds

67%

Shah K., Dubey R. S.

Acta Physiologiae Plantarum

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1998

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tom 20

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nr 2

When seeds of two rice cvs. Ratna and Jaya were germinated under increasing levels of cadmium nitrate (0, 100 and 500 µM) in the medium, a marked decrease in germination percentage was observed with Cd treatments, as compared to controls. There was more absorbed Cd in embryo axes than in endosperms. More uptake resulted with increasing Cd levels in the growth medium in embryo axes. In both rice cultivars, during a germination period of 0 – 120 h, an increased level of protein as well as free amino acids was noted in Cd treatments. Protease activity in general decreased in both embryo axes as well as endosperms due to Cd treatment. In vitro studies showed an enhancement in protease activity in Cd treatments at low Cd levels (50–100 µM), whereas concentrations above this caused inhibition in enzyme activity. Under 500 µM Cd treatments in vivo there was about 30 to 50 percent decline in leucine aminopeptidase (LAP) activity in endosperms, however, carboxypeptidase activity showed a marked increase in endosperms beyond 24 h under Cd treatments. In embryo axes of germinating seeds there was always a decline in peptidase activities, under the influence of cadmium. The leucine amino peptidase and protease activity were always greater in embryo axes in cv. Ratna than cv. Jaya. However, the carboxypeptidase activity was higher in Jaya when compared to Ratna in endosperms under Cd treatments. The results suggest possible suppression of protease and peptidase activities due to Cd treatments in germinating rice seeds leading to altered levels of protein and amino acids.

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Isoenzyme variation in the genetic resources of Vicia faba L.

67%

Przybylska J., Zimniak-Przybylska Z., Krajewski P.

Genetica Polonica

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1992

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tom 33

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