Isolation and Structures of Pipecolidepsins A and B, Cytotoxic Cyclic Depsipeptides from the Madagascan Sponge Homophymia lamellosa .
Laura Coello , Fernando Reyes , María Jesús Martín , Carmen Cuevas *, and Rogelio Fernández *
Medicinal Chemistry Department, PharmaMar S. A., Pol. Ind. La Mina Norte, Avenida de los Reyes 1, 28770, Colmenar Viejo (Madrid), Spain
Publication Date : January 24, 2014 .
Abstract :
Two new cyclic depsipeptides, Pipecolidepsins A and B (1 and 2), have been isolated from the sponge Homophymia lamellosa collected off the coast of Madagascar. Their structures were determined by a combination of NMR experiments and by LC-MS analysis of the amino acid fragments obtained by hydrolysis and derivatization using Marfey’s reagent. In addition to several common amino acids, these peptides contain unusual residues, including 2-amino-3-hydroxy-4,5-dimethylhexanoic acid, 3-ethoxyasparagine, 3,4-dimethylglutamine, 4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, and 3-hydroxyaspartic acid as well as a terminal 3-hydroxy-2,4,6-trimethylheptanoic acid residue. Pipecolidepsins A and B displayed cytotoxic activity against a panel of different human tumor cell lines.
Copyright © 2014 The American Chemical Society and American Society of Pharmacognosy .
Published: 27 January 2014 .
Carlos M. Galmarini , Maurizio D’Incalci and Paola Allavena .
Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment .
Abstract:
The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
Keywords: trabectedin; plitidepsin; tumor-associated macrophages; tumor microenvironment
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Conclusions :
In the last decades the concept that the tumor microenvironment is simply a supporting structure for the preservation of tissue architecture has dramatically changed. Indeed, microenvironmental components provide signals affecting cell adhesion, migration, proliferation, differentiation, and death. Monocytic-derived cells are key players of the cancer-related inflammation present at tumor sites. Such a reactive milieu eventually supports tumor cell proliferation and the full-blown development of neo-angiogenesis. There is increasing evidence that successful anti-cancer therapies are not only dependent on the cancer phenotype but also on the normalization of the tumor stroma. In this view, the findings showing that trabectedin and plitidepsin have wider mechanisms of action acting not only on tumor cells but also modifying the whole microenvironment is of great interest and may contribute to the development of new drugs from marine origin as anticancer therapies.
The opportunity to combine direct antiproliferative activity on tumor cells with the capacity to counteract the pro-tumoral properties of the tumor microenvironment is emerging as an especially appealing therapeutic effect of some drugs of marine origin. As reviewed above, the antitumor activity of trabectedin and plitidepsin is not only related to their effects on tumor cells, but also on their ability to affect the tumor microenvironment, in particular monocytic-derived cell (TAMs and NLCs, respectively) and their pro-tumoral functions. Of note, the effects of trabectedin on tumor microenvironment are in line with response patterns evident in several patients, such as tumor shrinkage or delayed response and prolonged stabilization even in the absence of evident tumor shrinkage [80]. Trabectedin can therefore be considered a particularly important antitumor agent with mechanisms of action that make it especially appropriate for targeting key processes in the biology of cancer. Similar considerations can be taken into account for plitidepsin.
To our knowledge, there are no other reports showing this specific activity with other marine-derived drugs. Therefore, whether this is a common feature of marine natural products or a specific mechanism for trabectedin and plitidepsin remains to be elucidated.
Future Directions :
Several questions need to be further addressed concerning the activity of drugs of marine origin on tumor microenvironment. We first need to understand if the activities observed for trabectedin or plitidepsin on the tumor microenvironment can be observed for other marine-derived drugs. A second question is whether these drugs are also affecting other stromal components besides the myeloid-derived compartment. We also need to understand whether the depletion of monocytic-derived cells is similar in all treated patients or if individual variability may result in different therapeutic efficacy. Another important question is whether, by affecting myeloid cells, marine-derived drugs independently influence main pathophysiological pathways of a given tumor. For example, it would be of interest to know if the anti-angiogenic activity of trabectedin is due to a direct effect on the vessel network or is mediated via the reduction of pro-angiogenic cytokines released by TAMs. While it is clear that marine-derived drugs have favorable mechanisms on tumor cells and the tumor microenvironment, additional research into the following actions would be beneficial. All these questions need to be addressed in order to improve the drug discovery and developmental process that would translate into more effective treatments with drugs of marine origin.
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Published: 27 January 2014 .
Abstract:
Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities.
Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with β-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition, cancer cells lacking mitochondrial DNA also exhibit cellular senescence upon LamD exposure indicating that LamD can trigger senescence, unlike apoptosis, in the absence of functional mitochondria. Overall, our results identify senescence-associated growth arrest as a powerful effect of LamD and add compelling evidence for the pharmacological interest of lamellarins as potential anticancer agents.
Keywords: oxidative stress response; mitochondria; DNA damage; cellular senescenc .
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Conclusions
In essence, our findings establish the marine drug, LamD, as a potential pro-senescent therapy against cancer and define the senescence program as a cellular stress response elicited by LamD. These results should reinforce our therapeutic interest for the lamellarin family of marine natural products.
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NGELES LÓPEZ. Madrid Actualizado: 28/01/2014 .
Es mucho todavía lo que queda por averiguar sobre el Alzheimer y otras enfermedades neurodegenerativas, pero los cientos de grupos que investigan sobre este tema arrojan, lentamente -sobre todo para pacientes y familiares-, cada vez más luz sobre sus posibles causas. Uno de esos trabajos es el que ahora publica la revista JAMA Neurology y que viene a incidir en la importancia del ambiente en este trastorno. Porque esta investigación ha identificado que haber estado expuesto a un pesticida como el DDT aumenta el riesgo de tener este trastorno.
El DDT, sintetizado por primera vez en 1874, fue utilizado ampliamente como insecticida agrícola y forestal a partir de 1939. Décadas más tarde diferentes estudios demostraron sus efectos nocivos sobre la salud y se fue prohibiendo paulatinamente en muchos países. Estados Unidos lo hizo en 1972 y España le siguió oficialmente a finales de esa década. Sin embargo, nuestro país siguió permitiendo el empleo de esta sustancia para elaborar dicofol, un plaguicida, y no fue hasta 2008 cuando lo prohibiría como sustancia intermediaria para el desarrollo de otros compuestos.
Quizás por este uso prolongado, por la comercialización ilegal o porque los metabolitos derivados del DDT, denominados DDE, permanecen varias décadas en el ambiente y en el organismo humano, varios estudios han constatado la presencia de estas sustancias en un gran número de personas. "Detectamos DDE en el 100% de la población española. En Cataluña se hizo un estudio representativo, donde se demostraba esta presencia, pero no es el único. Siempre que se ha estudiado una muestra poblacional se encuentra DDE en la totalidad de ellos, esto incluye a recién nacidos, lo que significa que el feto ha estado expuesto a esta sustancia durante el embarazo", afirma Miguel Porta, investigador del Instituto de Investigaciones Médicas del Hospital del Mar (IMIM).
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La tasa de mortalidad por cáncer en España ha disminuido un 13% en las dos últimas décadas, un porcentaje inferior al registrado en otros países europeos, como Francia, Italia, Alemania, Reino Unido o Bélgica, en los que el descenso se sitúa cerca del 20%. La primera causa de muerte por cáncer sigue siendo el de pulmón, que concentra un 20% de la mortalidad tumoral, seguido de los tumores colorrectales (el 14,3%) y, a bastante distancia, del cáncer de mama (5,9%).
Estos son algunos de los datos ofrecidos por la Sociedad Española de Oncología Médica (SEOM) en una rueda de prensa en la que su presidenta, Pilar Garrido, incidió en la importancia de que "se hable con normalidad de cáncer, no estigmatizarlo". En esta observación coincidió la expresidenta de la Comunidad de Madrid, Esperanza Aguirre, quien asistió al acto para manifestar su apoyo a los especialistas y sumarse a su petición de que sean registrados todos los casos de cáncer que se diagnostican en España, y no sólo el 15% de ellos, como sucede actualmente.
Los casos de cáncer aumentan año tras año, pero lo hacen debido al incremento de la población, la esperanza de vida y el envejecimiento. De ahí que una proporción muy alta de los tumores se registre en personas mayores de 65 años.
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Laura Coello , Fernando Reyes , María Jesús Martín , Carmen Cuevas *, and Rogelio Fernández * 
