Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

Abstract

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.

• Authors: Gwendoline Van Goietsenoven, Véronique Mathieu, Florence Lefranc, Alexander Kornienko, Antonio Evidente, Robert Kiss
• Journal: Medicinal research reviews (Med Res Rev) Vol. 33 Issue 2 Pg. 439-55 (Mar 2013) ISSN: 1098-1128 [Electronic] United States
• PMID: 22419031 (Publication Type: Journal Article, Review)
• Copyright: © 2012 Wiley Periodicals, Inc.

Chemical References

• Amaryllidaceae Alkaloids
• Cytotoxins
• Phenanthridines
• narciclasine
• GTP Phosphohydrolases

Topics

• Amaryllidaceae Alkaloids (adverse effects, pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, enzymology, pathology)
• Cohort Studies
• Cytotoxins (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• GTP Phosphohydrolases (drug effects, metabolism)
• Glioblastoma (drug therapy, enzymology, pathology)
• Humans
• In Vitro Techniques
• Melanoma (drug therapy, enzymology, pathology)
• Mice
• Molecular Targeted Therapy
• Neoplasms (drug therapy, pathology)
• Phenanthridines (adverse effects, pharmacology, therapeutic use)
• Structure-Activity Relationship
• Transplantation, Heterologous
• Treatment Outcome