Investigation of the marine compound spongistatin 1 links the inhibition of PKCα translocation to nonmitotic effects of tubulin antagonism in angiogenesis
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Citations
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References
Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: implications for cancer treatment.
Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to tubulin.
VASCULAR ENDOTHELIAL GROWTH FACTOR INDUCES PROTEIN KINASE C (PKC)-DEPENDENT Akt/PKB ACTIVATION AND PHOSPHATIDYLINOSITOL 3′-KINASE-MEDIATED PKCδ PHOSPHORYLATION: ROLE OF PKC IN ANGIOGENESIS
Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton.
Anticancer therapeutics: "Addictive" targets, multi-targeted drugs, new drug combinations.
Related Papers (5)
Frequently Asked Questions (15)
Q2. What is the effect of spongistatin 1 on endothelial cell?
the depolymerization of microtubules by spongistatin 1 might abrogate polarization in the endothelial cell and consequently reduce directed migration.
Q3. What is the role of spongistatin 1 in the apoptos?
Spongistatin 1 inhibits migration of endothelial cells and influences F-actin organizationMigration is a crucial step in angiogenesis.
Q4. What is the effect of spongistatin 1 on endothelial cells?
Spongistatin 1 is antiproliferative at a nontoxic concentrationAntiproliferative effects of spongistatin 1 on endothelial cells were investigated in a cell viability assay, DNA-fragmentation analysis, proliferation assay, and cell cycle analysis.
Q5. What is the role of spongistatin 1 in the neovascular?
Spongistatin 1 inhibits the translocation of PKC to the membraneBecause most of the PKC isoforms have to be translocated from the cytoplasm to membranes to become activated and translocation processes can depend on microtubules, the tubulin antagonist spongistatin 1 may influence the activity of specific PKC isoforms via inhibition of their transport to membranes.
Q6. At what concentration did spongistatin 1 cause apoptosis?
Acute cytotoxicity of spongistatin 1 on proliferating cells was observed at a concentration as low as 5.0 nM, as judged by the significant decrease in the metabolic activity of spongistatin 1-treated cells.
Q7. What is the effect of spongistatin 1 on PKC activity?
The well-established kinase inhibitor staurosporine, which is known to inhibit PKC activity by binding the ATP-site, caused complete inhibition of PKC serine-substrate phosphorylation, whereas spongistatin 1 reduced phosphorylation of not all but of distinct serine substrates (arrows in Fig. 7A).
Q8. What is the effect of spongistatin 1 on angiogenesis?
To identify microtubule-dependent signaling pathways involved in the initiation phase of angiogenesis and that might be affected by tubulin antagonism, a kinome array (PepChip) with spongistatin 1-, vinblastine-, or CA4P-treated HUVECs was performed.
Q9. What is the role of tubulin antagonists in angiogenesis?
inhibition of interphase microtubules by tubulin antagonists and subsequently reduced PKC translocation might provide a new mechanism by which tubulin antagonists act on angiogenesis.
Q10. How long did the spongistatin 1 treatment last?
Spongistatin 1 was administered intraperitoneally at a dose of 10 g/kg (dissolved in 2% dimethyl sulfoxide and isotonic saline) daily for 5 days, beginning from the first postoperative day (n 5).
Q11. What is the effect of spongistatin 1 on aortic ring?
Treatment of the aortic rings with 0.5 nM spongistatin 1 yielded reduced sprout formation, which was completely suppressed by treatment with 1.0 nM spongistatin 1 (Fig. 5C).
Q12. What is the effect of paclitaxel on endothelial cells?
As was to be expected, the microtubule-stabilizing compound paclitaxel caused an increase of tubulin in the fraction of polymerized microtubules.
Q13. What is the role of spongistatin 1 in the treatment of angiogenesis?
Meeting the increasing demand for new appropriate drugs for antiangiogenic therapy, this study presents the marine compound spongistatin 1 to be a strong antiangiogenic agent both in vitro and in vivo.
Q14. At what concentration did spongistatin 1 inhibit endothelial cells?
proliferation of HUVECs was already inhibited at a concentration as low as 100 pM spongistatin 1, whereas more than 25–500 higher concentrations of vinblastine (2.5 nM), C4AP (7.5 nM), or paclitaxel (50.0 nM), respectively, were needed to inhibit endothelial proliferation to a similar degree (Fig. 2C).
Q15. What was the protocol for -slide chemotaxis?
Cell tracking and analysis were done using the manual tracking plug-in (Fabrice Cordelieres, Orsay, France) and the chemotaxis and migration tool (IBIDI) for ImageJ (U.S. National Institutes of Health, Bethesda, MD, USA), as described in the -slide chemotaxis protocol.