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.
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.
Laboratoire de Chimie Analytique, Toxicologie et Chimie Physique Appliqueé, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Delphine
D
Lamoral-Theys
Anna
A
Andolfi
Gwendoline
G
Van Goietsenoven
Alessio
A
Cimmino
Benjamin
B
Le Calvé
Nathalie
N
Wauthoz
Véronique
V
Mégalizzi
Thierry
T
Gras
Céline
C
Bruyère
Jacques
J
Dubois
Véronique
V
Mathieu
Alexander
A
Kornienko
Robert
R
Kiss
Antonio
A
Evidente
D000199:Actins / Q000378:metabolism; D047151:Amaryllidaceae Alkaloids / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000199:Actins; D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; D010617:Phenanthridines; C015330:lycorine