Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight

Delphine Lamoral-Theys, Anna Andolfi, Gwendoline Van Goietsenoven, Alessio Cimmino, Benjamin Le Calvé, Nathalie Wauthoz, Véronique Mégalizzi, Thierry Gras, Céline Bruyère, Jacques Dubois, Véronique Mathieu, Alexander Kornienko, Robert Kiss, Antonio Evidente

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.

langue originaleAnglais
Pages (de - à)6244-56
Nombre de pages13
journalJournal of Medicinal Chemistry
Volume52
Numéro de publication20
Les DOIs
étatPublié - 2009
Modification externeOui

Empreinte digitale

Amaryllidaceae Alkaloids
Phenanthridines
Structure-Activity Relationship
Neoplasms
Melanoma
Cell Line
Cytostatic Agents
Glioblastoma
lycorine
Non-Small Cell Lung Carcinoma
Transplants

Citer ceci

Lamoral-Theys, Delphine ; Andolfi, Anna ; Van Goietsenoven, Gwendoline ; Cimmino, Alessio ; Le Calvé, Benjamin ; Wauthoz, Nathalie ; Mégalizzi, Véronique ; Gras, Thierry ; Bruyère, Céline ; Dubois, Jacques ; Mathieu, Véronique ; Kornienko, Alexander ; Kiss, Robert ; Evidente, Antonio. / Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli : an investigation of structure-activity relationship and mechanistic insight. Dans: Journal of Medicinal Chemistry. 2009 ; Vol 52, Numéro 20. p. 6244-56.
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title = "Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight",
abstract = "Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.",
keywords = "Actins, Amaryllidaceae Alkaloids, Animals, Antineoplastic Agents, Apoptosis, Cell Movement, Cell Proliferation, Cytoskeleton, Drug Resistance, Neoplasm, Female, Humans, Inhibitory Concentration 50, Maximum Tolerated Dose, Melanoma, Mice, Phenanthridines, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",
author = "Delphine Lamoral-Theys and Anna Andolfi and {Van Goietsenoven}, Gwendoline and Alessio Cimmino and {Le Calv{\'e}}, Benjamin and Nathalie Wauthoz and V{\'e}ronique M{\'e}galizzi and Thierry Gras and C{\'e}line Bruy{\`e}re and Jacques Dubois and V{\'e}ronique Mathieu and Alexander Kornienko and Robert Kiss and Antonio Evidente",
year = "2009",
doi = "10.1021/jm901031h",
language = "English",
volume = "52",
pages = "6244--56",
journal = "J. Med. Chem.",
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Lamoral-Theys, D, Andolfi, A, Van Goietsenoven, G, Cimmino, A, Le Calvé, B, Wauthoz, N, Mégalizzi, V, Gras, T, Bruyère, C, Dubois, J, Mathieu, V, Kornienko, A, Kiss, R & Evidente, A 2009, 'Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight', Journal of Medicinal Chemistry, VOL. 52, Numéro 20, p. 6244-56. https://doi.org/10.1021/jm901031h

Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli : an investigation of structure-activity relationship and mechanistic insight. / Lamoral-Theys, Delphine; Andolfi, Anna; Van Goietsenoven, Gwendoline; Cimmino, Alessio; Le Calvé, Benjamin; Wauthoz, Nathalie; Mégalizzi, Véronique; Gras, Thierry; Bruyère, Céline; Dubois, Jacques; Mathieu, Véronique; Kornienko, Alexander; Kiss, Robert; Evidente, Antonio.

Dans: Journal of Medicinal Chemistry, Vol 52, Numéro 20, 2009, p. 6244-56.

Résultats de recherche: Contribution à un journal/une revueArticle

TY - JOUR

T1 - Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli

T2 - an investigation of structure-activity relationship and mechanistic insight

AU - Lamoral-Theys, Delphine

AU - Andolfi, Anna

AU - Van Goietsenoven, Gwendoline

AU - Cimmino, Alessio

AU - Le Calvé, Benjamin

AU - Wauthoz, Nathalie

AU - Mégalizzi, Véronique

AU - Gras, Thierry

AU - Bruyère, Céline

AU - Dubois, Jacques

AU - Mathieu, Véronique

AU - Kornienko, Alexander

AU - Kiss, Robert

AU - Evidente, Antonio

PY - 2009

Y1 - 2009

N2 - Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.

AB - Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.

KW - Actins

KW - Amaryllidaceae Alkaloids

KW - Animals

KW - Antineoplastic Agents

KW - Apoptosis

KW - Cell Movement

KW - Cell Proliferation

KW - Cytoskeleton

KW - Drug Resistance, Neoplasm

KW - Female

KW - Humans

KW - Inhibitory Concentration 50

KW - Maximum Tolerated Dose

KW - Melanoma

KW - Mice

KW - Phenanthridines

KW - Structure-Activity Relationship

KW - Xenograft Model Antitumor Assays

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

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DO - 10.1021/jm901031h

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C2 - 19788245

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EP - 6256

JO - J. Med. Chem.

JF - J. Med. Chem.

SN - 0022-2623

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