| Autor: |
Pimentel, Adriana, Felibertt, Pimali, Sojo, Felipe, Colman, Laura, Mayora, Adriana, Silva, May, Rojas, Hector, Dipolo, Reinaldo, Suarez, Alírica, Compagnone, Reinaldo, Arvelo, Francisco, Galindo-Castro, Ivan, Sanctis, Juan, Chirino, Perla, Benaim, Gustavo |
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| Zdroj: |
Cancer Chemotherapy & Pharmacology; Jan2012, Vol. 69 Issue 1, p71-83, 13p |
| Abstrakt: |
Purpose: In search for new drugs derived from natural products for the possible treatment of cancer, we studied the action of agelasine B, a compound purified from a marine sponge Agelas clathrodes. Methods: Agelasine B was purified from a marine sponge Agelas clathrodes and assayed for cytotoxicity by MTT on two human breast cancer cells (MCF-7 and SKBr3), on a prostate cancer cells (PC-3) and on human fibroblasts. Changes in the intracellular Ca concentrations were assessed with FURA 2 and by confocal microscopy. Determination of Ca-ATPase activity was followed by Pi measurements. Changes in the mitochondria electrochemical potential was followed with Rhodamine 123. Apoptosis and DNA fragmentation were determined by TUNEL experiments. Results: Upon agelasine B treatment, cell viability of both human breast cancer cell lines was one order of magnitude lower as compared with fibroblasts (IC for MCF-7 = 2.99 μM; SKBr3: IC = 3.22 μM vs. fibroblasts: IC = 32.91 μM), while the IC for PC-3 IC = 6.86 μM. Agelasine B induced a large increase in the intracellular Ca concentration in MCF-7, SKBr3, and PC-3 cells. By the use of confocal microscopy coupled to a perfusion system, we could observe that this toxin releases Ca from the endoplasmic reticulum (ER). We also demonstrated that agelasine B produces a potent inhibition of the ER Ca-ATPase (SERCA), and that this compound induced the fragmentation of DNA. Accordingly, agelasine B reduced the expression of the anti-apoptotic protein Bcl-2 and was able to activate caspase 8, without affecting the activity of caspase 7. Conclusions: Agelasine B in MCF-7 cells induce the activation of apoptosis in response to a sustained increase in the [Ca] after blocking the SERCA activity. The reproduction of the effects of agelasine B on cell viability and on the [Ca] obtained on SKBr3 and PC-3 cancer cells strongly suggests the generality of the mechanism of action of this toxin. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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