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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Pro-apoptotic and anti-apoptotic molecules affecting pathways of signal transduction
1Research 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
Abstract:
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.
Insights
Targeting tyrosine kinases with novel inhibitors and TT-232 induces apoptosis in cancer cells. These compounds show tumor growth inhibition in vivo, offering new chemotherapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Modern chemotherapy often targets tyrosine kinases to inhibit cancer cell proliferation and induce apoptosis by depleting survival factors.
- Tyrosine kinase inhibitors (TKIs) are a significant class of anticancer agents, but their efficacy and mechanisms require continuous investigation.
Purpose of the Study:
- To synthesize and evaluate novel tyrosine kinase inhibitors for their ability to induce apoptosis in cancer cells.
- To investigate the apoptosis-inducing effects of the somatostatin analogue oligopeptide TT-232 and (-)-deprenyl on tumor cells.
Main Methods:
- Synthesis of potent tyrosine kinase inhibitors.
- In vitro testing of compounds for apoptosis and cytoplasmic vacuolar cell death induction in various tumor cell cultures.
- In vivo experiments using human tumor xenografts to assess tumor growth inhibition.
- Analysis of (-)-deprenyl's dose-dependent effects and its mechanism involving mitochondrial membrane depolarization.
Main Results:
- Several synthesized tyrosine kinase inhibitors induced apoptotic or cytoplasmic vacuolar cell death in tumor cell lines.
- The somatostatin analogue TT-232 demonstrated a dose-dependent apoptosis-inducing effect and significant tumor growth inhibition in vivo.
- (-)-deprenyl exhibited dose-dependent pro- or anti-apoptotic activity in melanoma cells, linked to mitochondrial membrane depolarization.
Conclusions:
- Targeting tyrosine kinases and related signaling pathways is a viable strategy for inducing cancer cell apoptosis.
- TT-232 and certain TKIs show promise as therapeutic agents, with demonstrated efficacy in both in vitro and in vivo models.
- The findings highlight the complex roles of compounds like (-)-deprenyl and the central involvement of caspase 3 in mediating apoptosis.
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