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Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux.
Cancer Lett. 2005 Apr 28; 221(2):165-75.CL

Abstract

Lamellarin D (LAM-D) is a marine alkaloid endowed with potent cytotoxic activities against various tumor cells, in particular human prostate cancer cells and leukemia cells. Its cytotoxic action is dependent, at least in part, to its capacity to inhibit topoisomerase I. P388CPT5 murine leukemia cells resistant to the reference topoisomerase I poison camptothecin (CPT) are cross-resistant to LAM-D but the relative resistance index (RRI) is significantly reduced with LAM-D (RRI=21) compared to CPT (RRI=103). To comprehend further the mechanism of action of this novel marine antitumor agent, we have investigated the influence of the P glycoprotein (Pgp) on the cytotoxicity of LAM-D and the proapoptotic effects induced by the alkaloid. P388CPT5 cells, expressing a mutated top1 gene, display a functional Pgp, as judged from cytometry experiments performed with cells treated with rhodamine 123 or calcein-ester whereas no Pgp activity was detected with the parental P388 cells. P388CPT5 cells are also cross-resistant to the topoisomerase II poisons doxorubicin and etoposide but the resistance is abolished in the presence of verapamil or quinine (at non toxic concentrations) which reverse the multidrug resistance (MDR) phenotype. In contrast, the RRI measured with LAM-D and CPT remain unchanged in the presence of the two MDR reversal agents. The effects of LAM-D on the cell cycle progression were different in the parental P388 cells compared with the CPT-resistant which were blocked in the S and subsequently G2-M phases of the cell cycle. Cytometry experiments with the JC-1 fluorescent marker revealed that LAM-D and CPT promoted apoptosis in parental P388 cells via an activation of the mitochondrial pathway. In contrast, a massive depolarisation of the mitochondrial membrane potential and a nuclear fragmentation were detected only with LAM-D on P388CPT5 cells. This in vitro work identifies LAM-D as a potent pro-apoptotic agent and its cytotoxic action is fully maintained in multidrug-resistant cells compared to the sensitive parental cell line.

Authors+Show Affiliations

Centre Oscar Lambret and INSERM U-524, IRCL, Institute for Cancer Research, Place de Verdun, Lille cedex F-59045, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15808402

Citation

Vanhuyse, Marie, et al. "Lamellarin D: a Novel Pro-apoptotic Agent From Marine Origin Insensitive to P-glycoprotein-mediated Drug Efflux." Cancer Letters, vol. 221, no. 2, 2005, pp. 165-75.
Vanhuyse M, Kluza J, Tardy C, et al. Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux. Cancer Lett. 2005;221(2):165-75.
Vanhuyse, M., Kluza, J., Tardy, C., Otero, G., Cuevas, C., Bailly, C., & Lansiaux, A. (2005). Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux. Cancer Letters, 221(2), 165-75.
Vanhuyse M, et al. Lamellarin D: a Novel Pro-apoptotic Agent From Marine Origin Insensitive to P-glycoprotein-mediated Drug Efflux. Cancer Lett. 2005 Apr 28;221(2):165-75. PubMed PMID: 15808402.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lamellarin D: a novel pro-apoptotic agent from marine origin insensitive to P-glycoprotein-mediated drug efflux. AU - Vanhuyse,Marie, AU - Kluza,Jérôme, AU - Tardy,Christèle, AU - Otero,Gabriel, AU - Cuevas,Carmen, AU - Bailly,Christian, AU - Lansiaux,Amélie, PY - 2004/07/18/received PY - 2004/09/10/revised PY - 2004/09/13/accepted PY - 2005/4/6/pubmed PY - 2005/6/1/medline PY - 2005/4/6/entrez SP - 165 EP - 75 JF - Cancer letters JO - Cancer Lett. VL - 221 IS - 2 N2 - Lamellarin D (LAM-D) is a marine alkaloid endowed with potent cytotoxic activities against various tumor cells, in particular human prostate cancer cells and leukemia cells. Its cytotoxic action is dependent, at least in part, to its capacity to inhibit topoisomerase I. P388CPT5 murine leukemia cells resistant to the reference topoisomerase I poison camptothecin (CPT) are cross-resistant to LAM-D but the relative resistance index (RRI) is significantly reduced with LAM-D (RRI=21) compared to CPT (RRI=103). To comprehend further the mechanism of action of this novel marine antitumor agent, we have investigated the influence of the P glycoprotein (Pgp) on the cytotoxicity of LAM-D and the proapoptotic effects induced by the alkaloid. P388CPT5 cells, expressing a mutated top1 gene, display a functional Pgp, as judged from cytometry experiments performed with cells treated with rhodamine 123 or calcein-ester whereas no Pgp activity was detected with the parental P388 cells. P388CPT5 cells are also cross-resistant to the topoisomerase II poisons doxorubicin and etoposide but the resistance is abolished in the presence of verapamil or quinine (at non toxic concentrations) which reverse the multidrug resistance (MDR) phenotype. In contrast, the RRI measured with LAM-D and CPT remain unchanged in the presence of the two MDR reversal agents. The effects of LAM-D on the cell cycle progression were different in the parental P388 cells compared with the CPT-resistant which were blocked in the S and subsequently G2-M phases of the cell cycle. Cytometry experiments with the JC-1 fluorescent marker revealed that LAM-D and CPT promoted apoptosis in parental P388 cells via an activation of the mitochondrial pathway. In contrast, a massive depolarisation of the mitochondrial membrane potential and a nuclear fragmentation were detected only with LAM-D on P388CPT5 cells. This in vitro work identifies LAM-D as a potent pro-apoptotic agent and its cytotoxic action is fully maintained in multidrug-resistant cells compared to the sensitive parental cell line. SN - 0304-3835 UR - https://www.unboundmedicine.com/medline/citation/15808402/Lamellarin_D:_a_novel_pro_apoptotic_agent_from_marine_origin_insensitive_to_P_glycoprotein_mediated_drug_efflux_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3835(04)00731-1 DB - PRIME DP - Unbound Medicine ER -