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Narciclasine as well as other Amaryllidaceae Isocarbostyrils are Promising GTP‐ase Targeting Agents against Brain Cancers
Author(s) -
Van Goietsenoven Gwendoline,
Mathieu Véronique,
Lefranc Florence,
Kornienko Alexander,
Evidente Antonio,
Kiss Robert
Publication year - 2013
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21253
Subject(s) - in vivo , pharmacology , rhoa , in vitro , medicine , melanoma , cytotoxic t cell , cancer research , biology , biochemistry , signal transduction , microbiology and biotechnology
The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μ M 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 n M 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 GTP ases, including R hoA and the elongation factor e EF 1 A . 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.