Novel advances in the regulation of signal transduction activity

George Weber, Fei Shen, Wei Li, Noemi Prajda, Lehel Hullan, Hongyuan Yang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Novel advances have been made in the characterization of signal transduction activity of normal human breast parenchymal (HMEC) and human breast carcinoma MCF-7 and MDA-MB-435 cells. The IP3 concentration was increased 2-fold in human breast carcinomas. Thus, the elevated signal transduction enzymic activities were reflected in the higher concentrations of the second messenger, I P3, in human breast carcinoma samples. Novel observations were presented on the impact of a combination of inhibitors of signal transduction, quercetin and genistein, in the treatment of human ovarian carcinoma cells. The two drugs inhibited PI kinase and PIP kinase, respectively, and as single agents reduced enzyme activities and IP3 concentration. When the drugs were administered sequentially, synergistic growth inhibition and cytotoxicity were observed. Sequential administration also yielded synergistic reduction of IP3 concentration. Since the cytotoxicity of quercetin is enhanced synergistically by genistein, lower concentrations of each drug may be used, decreasing potential side effects. This novel combination of quercetin and genistein should be of interest for clinical trials on ovarian carcinomas, also because novel targets in signal transduction are provided. Observations were presented on the impact of a combination of tiazofurin and genistein which was tested in view of their different mechanisms of action in reducing IP3 concentration and inducing differentiation and apoptosis. When tiazofurin and genistein were administered sequentially, synergistic growth inhibition and cytotoxicity were observed. Since the cytotoxicity of tiazofurin is synergistically enhanced by genistein, lower concentrations of tiazofurin may be employed, thus decreasing potential side effects. The antiproliferative action of tiazofurin depends on reduction of GTP concentration and the subsequent lowering of IP3 levels. By contrast, the antiproliferative action of the flavonoids entails the inhibition by quercetin of PI kinase activity and by genistein of PIP kinase activity. These enzyme inhibitors are responsible for the reduction of IP3 concentration. The novel combination of tiazofurin and genistein should be of interest for the clinical trials on leukemia and also in ovarian carcinomas. The utilization of these drugs is also of relevance because novel targets in signal transduction are provided and these biochemical targets may also be used in monitoring the impact of therapy and in heralding impending relapse.

Original languageEnglish
Pages (from-to)49-62
Number of pages14
JournalAdvances in Enzyme Regulation
Volume38
Issue number1
DOIs
StatePublished - Jul 1998

Fingerprint

tiazofurin
Signal transduction
Genistein
Signal Transduction
Quercetin
Cytotoxicity
Phosphotransferases
Breast Neoplasms
Carcinoma
Pharmaceutical Preparations
Clinical Trials
Drug Utilization
Enzyme activity
Second Messenger Systems
Enzyme Inhibitors
Growth
Guanosine Triphosphate
Flavonoids
Human Activities
Leukemia

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Novel advances in the regulation of signal transduction activity. / Weber, George; Shen, Fei; Li, Wei; Prajda, Noemi; Hullan, Lehel; Yang, Hongyuan.

In: Advances in Enzyme Regulation, Vol. 38, No. 1, 07.1998, p. 49-62.

Research output: Contribution to journalArticle

Weber, G, Shen, F, Li, W, Prajda, N, Hullan, L & Yang, H 1998, 'Novel advances in the regulation of signal transduction activity', Advances in Enzyme Regulation, vol. 38, no. 1, pp. 49-62. https://doi.org/10.1016/S0065-2571(98)00002-8
Weber, George ; Shen, Fei ; Li, Wei ; Prajda, Noemi ; Hullan, Lehel ; Yang, Hongyuan. / Novel advances in the regulation of signal transduction activity. In: Advances in Enzyme Regulation. 1998 ; Vol. 38, No. 1. pp. 49-62.
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