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Title

Effects of N(8)-acetylspermidine deacetylase inhibition on growth and differentiation of PC12 cells

Date of Award

1993

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Abstract

Induction of neurite outgrowths is a well documented effect of nerve growth factor (NGF) on PC12 cells. NGF at 50 ng/ml induced neurite outgrowths in about 90% of the cells after 8 days of treatment. In addition to morphological differentiation, we observed a significant (p $<$ 0.01) decrease in the rate of growth of the cells. Inhibition of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase, by DFMO significantly (p $<$ 0.01) inhibited the growth of PC12 cells and slightly inhibited morphological differentiation induced by NGF. An inhibitor of N$\sp8$-acetylspermidine deacetylase, 7-(N-(3-aminopropyl)amino) heptan-2-one (APAH), was used to study the effects of N$\sp8$-acetylspermidine on growth and differentiation of PC12 cells. APAH was found to stimulate the growth rate and induce morphological differentiation of these cells. Maximum cell densities were increased (p $<$ 0.01) by 17.01%, 12.32% and 24.05% compared to control at concentrations of 10$\sp{-5}$ M, 10$\sp{-6}$ M, and 10$\sp{-7}$ M APAH, respectively. Maximum cell differentiation was observed about 8 days after initiation of treatment. At concentrations of 10$\sp{-5}$ M, 10$\sp{-6}$ M, and 10$\sp{-7}$ M APAH, 30.37%, 26.5%, and 34% of the cells were differentiated, respectively. Coaddition of APAH and NGF to the medium inhibited the cell growth and this inhibition was about the same as the inhibition induced by NGF alone. N$\sp8$-acetylspermidine increased cell growth at concentrations of 10$\sp{-5}$ M, 10$\sp{-6}$ M, and 10$\sp{-7}$ M. However, a significant increase was observed only from day 4 to day 7 of treatment. When the cells received simultaneous treatment with APAH and N$\sp8$-acetylspermidine, a small synergistic effect on the stimulation of cell growth and morphological differentiation was observed. Genistein, an inhibitor of protein tyrosine kinase, is known to inhibit cell growth and induce differentiation of some cell lines. At a concentration of 40 $\mu$g/ml, inhibition of PC12 cell growth (p $<$ 0.01) was observed but the morphological differentiation of the cells was not induced. The combination of genistein and NGF led to inhibition of cell growth not significantly different from the inhibition induced by NGF alone. When added in the presence of APAH, genistein showed inhibition of cell growth similar to the growth observed by genistein alone and morphological differentiation was about the same as the differentiation induced by APAH. (Abstract shortened by UMI.)

Pages

99

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