Narciclasine as well as other Amaryllidaceae Isocarbostyrils are Promising GTP-ase Targeting Agents against Brain Cancers

• Published in: Medicinal research reviews 2013-03, Vol.33 (2), p.439-455
• Main Authors: Van Goietsenoven, Gwendoline, Mathieu, Véronique, Lefranc, Florence, Kornienko, Alexander, Evidente, Antonio, Kiss, Robert
• Format: Article
• Language: English
• Subjects: actin cytoskeleton; Amaryllidaceae Alkaloids - adverse effects; Amaryllidaceae Alkaloids - pharmacology; Amaryllidaceae Alkaloids - therapeutic use; Amaryllidaceae isocarbostyril; Animals; Apoptosis - drug effects; apoptosis resistance; Brain cancer; brain metastases; Brain Neoplasms - drug therapy; Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Cancer; Chemotherapy; Cohort Studies; Cytotoxicity; Cytotoxins - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; eEF1A; Glioblastoma - drug therapy; Glioblastoma - enzymology; Glioblastoma - pathology; glioma; GTP Phosphohydrolases - drug effects; GTP Phosphohydrolases - metabolism; GTPases; Humans; In Vitro Techniques; Melanoma - drug therapy; Melanoma - enzymology; Melanoma - pathology; Mice; Molecular Targeted Therapy; narciclasine; Neoplasms - drug therapy; Neoplasms - pathology; pancratistatin; Phenanthridines - adverse effects; Phenanthridines - pharmacology; Phenanthridines - therapeutic use; RhoA; Structure-Activity Relationship; Toxicity; Transplantation, Heterologous; Treatment Outcome
• ISSN: 0198-6325; 1098-1128
• DOI: 10.1002/med.21253

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.