Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells.
Cell motility and resistance to apoptosis characterize glioblastoma multiforme growth and malignancy. Narciclasine, a plant growth modulator, could represent a powerful new weapon targeting the Achilles' heel of glioblastoma multiforme and may offer the potential to better combat these devastating malignancies. The in vitro effects of narciclasine on cell proliferation, morphology, actin cytoskeleton organization, and the Rho/Rho kinase/LIM kinase/cofilin pathway and its antitumor activity in vivo have been determined in models of human glioblastoma multiforme. Narciclasine impairs glioblastoma multiforme growth by markedly decreasing mitotic rates without inducing apoptosis. The compound also modulates the Rho/Rho kinase/LIM kinase/cofilin signaling pathway, greatly increasing GTPase RhoA activity as well as inducing actin stress fiber formation in a RhoA-dependent manner. Lastly, the treatment of human glioblastoma multiforme orthotopic xenograft- bearing mice with nontoxic doses of narciclasine significantly increased their survival. Narciclasine antitumor effects were of the same magnitude as those of temozolomide, the drug associated with the highest therapeutic benefits in treating glioblastoma multiforme patients. Our results show for the first time that narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma multiforme cells and significantly increases the survival of human glioblastoma multiforme preclinical models. This statement is made despite the recognition that to date, irrespective of treatment, no single glioblastoma multiforme patient has been cured.
Lefranc
Florence
F
Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Campus de la Plaine, Boulevard du Triomphe, Brussels, Belgium.
Sauvage
Sébastien
S
Van Goietsenoven
Gwendoline
G
Mégalizzi
Véronique
V
Lamoral-Theys
Delphine
D
Debeir
Olivier
O
Spiegl-Kreinecker
Sabine
S
Berger
Walter
W
Mathieu
Véronique
V
Decaestecker
Christine
C
Kiss
Robert
R
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism*; D051345:Destrin / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010617:Phenanthridines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010937:Plant Growth Regulators / Q000494:pharmacology*; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D000199:Actins; D047151:Amaryllidaceae Alkaloids; D051345:Destrin; C495825:Dstn protein, mouse; D010617:Phenanthridines; D010937:Plant Growth Regulators; C010753:narciclasine; D054461:Lim Kinases; D054460:rho-Associated Kinases