The marine sponge toxin agelasine B increases the intracellular Ca(2+) concentration and induces apoptosis in human breast cancer cells (MCF-7).

Abstract

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(2+) concentrations were assessed with FURA 2 and by confocal microscopy. Determination of Ca(2+)-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(50) for MCF-7 = 2.99 μM; SKBr3: IC(50) = 3.22 μM vs. fibroblasts: IC(50) = 32.91 μM), while the IC(50) for PC-3 IC(50) = 6.86 μM. Agelasine B induced a large increase in the intracellular Ca(2+) 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(2+) from the endoplasmic reticulum (ER). We also demonstrated that agelasine B produces a potent inhibition of the ER Ca(2+)-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(2+)]( i ) after blocking the SERCA activity. The reproduction of the effects of agelasine B on cell viability and on the [Ca(2+)]( I ) obtained on SKBr3 and PC-3 cancer cells strongly suggests the generality of the mechanism of action of this toxin.

• Authors: Adriana A Pimentel, Pimali Felibertt, Felipe Sojo, Laura Colman, Adriana Mayora, May Li Silva, Hector Rojas, Reinaldo Dipolo, Alírica I Suarez, Reinaldo S Compagnone, Francisco Arvelo, Ivan Galindo-Castro, Juan B De Sanctis, Perla Chirino, Gustavo Benaim
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 1 Pg. 71-83 (Jan 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 21603866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Naphthalenes
• Purines
• agelasine B
• Calcium

Topics

• Agelas (chemistry)
• Animals
• Antineoplastic Agents (administration & dosage, isolation & purification, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Calcium (metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Female
• Fibroblasts (drug effects, metabolism)
• Humans
• In Situ Nick-End Labeling
• Inhibitory Concentration 50
• Male
• Microscopy, Confocal
• Naphthalenes (administration & dosage, isolation & purification, pharmacology)
• Prostatic Neoplasms (drug therapy, pathology)
• Purines (administration & dosage, isolation & purification, pharmacology)