Pro-apoptotic and anti-apoptotic molecules affecting pathways of signal transduction.
Selective inhibition of the "false" proliferative signals via targeting tyrosine kinases resulting in the induction of apoptosis by depletion of the "survival factors" is one of the most studied and widely accepted concepts of modern chemotherapy. We have synthesized a series of potent tyrosine kinase inhibitors and tested these compounds for apoptosis induction. Some of the tyrosine kinase inhibitors caused either apoptotic or cytoplasmic vacuolar cell death in various tumor cell cultures. The somatostatin analogue oligopeptide TT-232, which indirectly inhibits tyrosine kinases, exerted a dose-dependent apoptosis-inducing effect. The tumor growth-inhibitory effect of TT-232 and some tyrosine kinase inhibitors has also been proven by in vivo experiments, using human tumor xenografts. On the other hand, a dose-dependent pro- or anti-apoptotic activity of (-)-deprenyl has been shown in melanoma cell cultures, the lower doses inhibiting and the higher doses inducing apoptosis. Various metabolites of (-)-deprenyl are responsible for these actions. The effect of (-)-deprenyl is connected with depolarization of mitochondrial membranes. The kinase inhibitors act on the growth factor receptor signaling pathways (survival factor pathways) and initiate the caspase cascade. The key enzyme for the action of both pro-apoptotic and anti-apoptotic compounds is caspase 3.
Kéri
G
G
Research Group of Peptide Biochemistry of Hungarian Academy of Sciences in the Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. keri@puskin.sote.hu
Racz
G
G
Magyar
K
K
Orfi
L
L
Horváth
A
A
Schwab
R
R
Hegymegi
B B
BB
Szende
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D010456:Peptides, Cyclic / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D012642:Selegiline / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013004:Somatostatin / Q000031:analogs & derivatives; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C060152:tyrphostin 47; D012642:Selegiline; C094462:TT2-32; D013004:Somatostatin