Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma

Malformations and growth disturbances are two- to threefold more common in infants of diabetic mothers than in offspring of non-diabetic pregnancy. Several suggestions have emerged to explain the reasons for diabetic embryopathy, including enhanced mitochondrial production of reactive oxygen species leading to altered activation of protein kinase C. This study aimed to evaluate the effect of α-cyano-4-hydroxycinnamic acid (CHC) and N-acetylcysteine (NAC) addition on morphology and activity of protein kinase C-δ and protein kinase C-ζ in rat embryos exposed to a high glucose concentration in vitro. Day 9 embryos from normal rats were cultured in 10 or 30 mM glucose concentrations with or without supplementation of CHC, NAC, or protein kinase C inhibitors specific for protein kinase C-δ and protein kinase C-ζ. Embryos were evaluated for malformations, crown rump length, and somite number. Protein kinase C-δ and protein kinase C-ζ activities were estimated by western blot by separating membranous and cytosolic fractions of the embryo. We found increased malformations and growth retardation in embryos cultured in high versus low glucose concentrations. These abnormalities were diminished when CHC and NAC or specific protein kinase C-inhibitors were added to the culture medium. The activities of embryonic protein kinase C-δ and protein kinase C-ζ were increased in the high glucose environment after 24-h culture, but were normalized by the addition of CHC and NAC as well as respective inhibitor to the culture medium. These findings suggest that mitochondrial overproduction of reactive oxygen species is involved in diabetic embryopathy. Furthermore, such overproduction may affect embryonic development, at least partly, by enhancing the activities of protein kinase C-δ and protein kinase C-ζ.

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Protein kinase C inhibitors for immune disorders

Drug Discovery Today ◽

10.1016/j.drudis.2014.05.008 ◽

2014 ◽

Vol 19 (8) ◽

pp. 1217-1221 ◽

Cited By ~ 18

Author(s):

Amnon Altman ◽

Kok-Fai Kong

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Immune Disorders ◽

Protein Kinase C Inhibitors ◽

Kinase C

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Activation of Protein Kinase C Increases Neuronal Excitability by Regulating Persistent Na+ Current in Mouse Neocortical Slices

Journal of Neurophysiology ◽

10.1152/jn.1998.80.3.1547 ◽

1998 ◽

Vol 80 (3) ◽

pp. 1547-1551 ◽

Cited By ~ 57

Author(s):

Nadav Astman ◽

Michael J. Gutnick ◽

Ilya A. Fleidervish

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Action Potential ◽

Neuronal Excitability ◽

Specific Protein ◽

Protein Kinase C Inhibitors ◽

Cationic Current ◽

Kinase C ◽

Layer V ◽

Neuronal Functions

Astman, Nadav, Michael J. Gutnick, and Ilya A. Fleidervish. Activation of protein kinase C increases neuronal excitability by regulating persistent Na+ current in mouse neocortical slices. J. Neurophysiol. 80: 1547–1551, 1998. Effects of the protein kinase C activating phorbol ester, phorbol 12-myristate 13-acetate (PMA), were studied in whole cell recordings from layer V neurons in slices of mouse somatosensory neocortex. PMA was applied intracellularly (100 nM to 1 μM) to restrict its action to the cell under study. In current-clamp recordings, it enhanced neuronal excitability by inducing a 10- to 20-mV decrease in voltage threshold for action-potential generation. Because spike threshold in neocortical neurons critically depends on the properties of persistent Na+ current ( I NaP), effects of PMA on this current were studied in voltage clamp. After blocking K+ and Ca2+ currents, I NaP was revealed by applying slow depolarizing voltage ramps from −70 to 0 mV. Intracellular PMA induced a decrease in I NaP at very depolarized membrane potentials. It also shifted activation of I NaP in the hyperpolarizing direction, however, such that there was a significant increase in persistent inward current at potentials more negative than −45 mV. When tetrodotoxin (TTX) was added to the bath, blocking I NaP and leaving only an outward nonspecific cationic current ( I cat), PMA had no apparent effect on responses to voltage ramps. Thus PMA did not affect I cat, and it did not induce any additional current. Intracellular application of the inactive PMA analogue, 4α-PMA, did not affect I NaP. The specific protein kinase C inhibitors, chelerythrine (20 μM) and calphostin C (10 μM), blocked the effect of PMA on I NaP. The data suggest that PMA enhances neuronal excitability via a protein kinase C–mediated increase in I NaP at functionally critical subthreshold voltages. This novel effect would modulate all neuronal functions that are influenced by I NaP, including synaptic integration and active backpropagation of action potential from the soma into the dendrites.

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