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
U2 - 10.1021/jm901031h
DO - 10.1021/jm901031h
M3 - Article
C2 - 19788245
SN - 0022-2623
VL - 52
SP - 6244
EP - 6256
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -