Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux

Vanhuyse, Marie; Kluza, Jérôme; Tardy, Claudine; Otero, Gabriel; Cuevas, Carmen; Bailly, Christian; Lansiaux, Amélie

doi:10.1016/j.canlet.2004.09.022

Cited by 84 publications

(68 citation statements)

References 26 publications

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“…1A) has been shown to inhibit a large panel of tumor cell types in vitro. At doses in the micromolar range, lamellarin D exhibits high apoptotic activities in leukemia cell lines (2,3) characterized by the dissipation of the mitochondrial membrane potential (Δψm), the release of cytochrome c from mitochondria, and caspase-3 activation (2). The proapoptotic effects of lamellarin D can result from several mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D

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Kluza

Martoriati

et al. 2009

Molecular Cancer Therapeutics

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Lamellarin D, a potent cytotoxic marine alkaloid, exerts its antitumor action through two complementary pathways: a nuclear route via topoisomerase I inhibition and a mitochondrial targeting. The present study was designed to investigate the contribution of these two pathways for apoptosis in cancer cells. Lamellarin D promoted nuclear apoptosis in leukemia cells without prominent cell cycle arrest. Signals transmitted by lamellarin D initiated apoptosis via the intrinsic apoptotic pathway. The drug induced conformational activation of Bax and decreased the expression levels of antiapoptotic proteins Bcl-2 and cIAP2 in association with activation of caspase-9 and caspase-3. Upon lamellarin D exposure, Fas and Fas-L expression was not modified in leukemia cells. Moreover, leukemia cells deficient in caspase-8 or Fas-associated protein with death domain underwent apoptosis through the typical mitochondrial apoptotic cascade, indicating that cell death induced by lamellarin D was independent of the extrinsic apoptotic pathway. Lamellarin D also exerted a topoisomerase I-mediated DNA damage response resulting in H2AX phosphorylation, and the upregulation of the DNA repair protein Rad51 and of p53, as well as the phosphorylation of p53 at serine 15. However, lamellarin D killed efficiently mutated p53 or p53 null cancer cells, and sensitivity to lamellarin D was abrogated neither by cycloheximide nor in enucleated cells. Lamellarin D-induced cytochrome c release occurs independently of nuclear factors in a cell-free system. These results suggest that lamellarin D exerts its cytotoxic effects primarily by inducing mitochondrial apoptosis independently of nuclear signaling. Thus, lamellarin D constitutes a new proapoptotic agent that may bypass certain forms of apoptosis resistance that occur in tumor cells.

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Section: Introductionmentioning

confidence: 99%

Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D

Ballot

Kluza

Martoriati

et al. 2009

Molecular Cancer Therapeutics

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“…27,[29][30][31] We have found at least two intracellular pathways in Vin R KB and Adr R MCF-7 cells that involve the increased level of GSH/GST activity and the overexpression of Bcl-2.…”

Section: Discussionmentioning

confidence: 97%

Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

Zhu

Liu²,

Zhao³

et al. 2006

Cancer Biology & Therapy

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Bicyclol, a second generation of synthetic hepatoprotectant being used in China for anti-hepatitis therapy, shows chemosensitizing effect on reverting multiple drug resistance (MDR) of cytostatic agents in two established MDR carcinoma cell lines, vincristine resistant human stomatic epidermoid carcinoma Vin R KB and adriamycin resistant human breast carcinoma Adr R MCF-7. The reversal rate of drug resistance was calculated from the changes of the IC 50 of cell growth inhibition. Bicyclol at the concentration of 25, 50, 100 µM induced 2.8 7.3 and 20.7 fold, respectively, reversal of vincristine resistance in Vin R KB cell. Bicyclol also reversed the cross-resistance of Vin R KB cell to taxol and Adr R MCF-7 cell resistance to adriamycin at the similar range of potency. Further, Bicyclol recovered the reduced accumulation of adriamycin in Adr R MCF-7 cell partially to the level in drugsensitive MCF-7 cell, indicate the inhibition of MDR related membrane efflux pump system. Overexpression of membrane p-glycoprotein coded by Mdr-1 genes, the most common efflux pump correlated to MDR, was found in both Vin R KB and Adr R MCF-7 cells by Western blot and immunocytochemistry as compared with drug-sensitive cells. The p-glycoprotein was decreased to the levels in drug-sensitive cells when Vin R KB and Adr R MCF-7 cells were treated with Bicyclol for 12-72 hours. Both Vin R KB and Adr R MCF-7 cells showed increased GSH contents, and Adr R MCF-7 cell showed increased GST activity and the overexpression of Bcl-2 protein, by which molecules are tightly related to the MDR formation besides Mdr-1 p-glycoprotein. Bicyclol reduced the GSH contents, GST activities and Bcl-2 expression. All these data demonstrate that, by modifying the expressions of Mdr-1, GSH/GST and Bcl-2, Bicyclol increases the intracellular drug concentration and sensitizes the resistant cells to the anti-carcinoma agents.

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“…Selected structures of lamellarins isolated from ascidians Following the discovery of the potent anti-proliferative and proapoptotic activities of lamellarins, their biological activities have been extensively studied, in particular their capacities to interfere with topoisomerase (TOPO) I and mitochondria, both contributing to their potent cytotoxicity. Although all the aspects of the lamellarins' mechanism of action are not completely known, it has been demonstrated that they are potent inhibitors of topoisomerase (TOPO) I, they interact with DNA, they target mitochondria directly, and they induce the release of cytochrome C and apoptosis-inducing factor (AIF) [51,[53][54][55][56][57][58]. Lamellarin D (81) was identified as a potent TOPO I poison in 2003 [53]; it binds relatively weakly to DNA, presumably via the insertion of its planar pentacyclic chromophore between DNA base pairs.…”

Section: Bis-steroidal Pyrazines: Ritterazines and Cephalostatins Pomentioning

confidence: 99%

“…Some lamellarins also function as multi-drug resistance (MDR) reversal drugs [51,56]. MDR is a term used to characterize the ability of tumors to exhibit simultaneous resistance to various chemotherapeutic agents through diverse mechanisms but, more frequently, through modification of drug efflux implicating ABC transporters, such as the multidrug resistance-associated protein (MRP) or P-glycoprotein (Pgp).…”

Section: Bis-steroidal Pyrazines: Ritterazines and Cephalostatins Pomentioning

confidence: 99%

“…In tumor cells expressing Pgp, the efflux of a given anticancer drug increases across the plasma membrane, thereby reducing the intracellular drug concentration and hence its cytotoxicity; Pgp activity can be reversed by a few specific molecules, referred to as MDR modulators. Lamellarins I (77), K (79), and T (80) have been reported to act as MDR modulators; these compounds exhibited equally effective cytotoxic activity against MDR cell lines and demonstrated that even at non-cytotoxic concentration they reverse MDR by inhibiting P-glycoprotein-mediated drug efflux [56]. It has been demonstrated that lamellarin I (77) reversed MDR by directly inhibiting the P-glycoprotein-mediated drug efflux at nontoxic doses and that the potency of lamellarin I as an MDR modulator was 9-16-fold higher than that of approved anticancer agent verapamil, resensitizing the resistant malignant cells to frontline therapeutics [51].…”

Section: Bis-steroidal Pyrazines: Ritterazines and Cephalostatins Pomentioning

confidence: 99%

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Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

et al. 2014

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Abstract:The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery.

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Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux

Cited by 84 publications

References 26 publications

Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D

Essential role of mitochondria in apoptosis of cancer cells induced by the marine alkaloid Lamellarin D

Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

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