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|Title:||A novel cycloheptapeptide exerts strong anticancer activity via stimulation of multiple apoptotic pathways in caspase-3 deficient cancer cells|
|Keywords:||Biochemistry, Genetics and Molecular Biology;Medicine|
|Citation:||Anticancer Research. Vol.27, No.4 B (2007), 2473-2479|
|Abstract:||Background: VR3848 is a novel cycloheptapeptide, isolated from a Euphorbiaceae plant, which can suppress proliferation of various tumor cells at nanomolar concentration. Due to its novelty and potency, the molecular process of tumor cell growth inhibition was investigated intensively. Materials and Methods: MCF-7 cells, a caspase-3 deficient cancer cell line, were treated with VR3848. The genetic response was monitored using cDNA array analysis. Results: Expression alterations of caspase, bcl-2 family members, death receptor, death adaptor, death ligands, stress response, cell cycle machinery, mitogen-activated protein kinases (MAPKs) and proto-oncogene were found which can be linked into three apoptotic pathways. The first was the death receptor-mediated pathway, which was confirmed by functional inhibition of caspase-8 and -10. The second pathway was via ER-stress apoptosis demonstrated by up-regulation of ER-stress genes and the release of caspase-12 into the cytoplasm. The third pathway involved mitochondrial membrane leakage which was elucidated by down-regulation of anti-apoptotic bcl-2 and an increased level of cytosolic apoptosis-inducing factor (AIF). Cell cycle arrest was observed which may have been a direct effect of VR3848 or a consequence of DNA strand breaks which in turn stimulated cell cycle arrest. Conclusion: VR3848 inhibited MCF-7 cancer cell growth through an activation of three related apoptotic pathways.|
|Appears in Collections:||Scopus 2006-2010|
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