Narciclasine
Description:
IC50: The mean IC50 of about 50 nmol/L calculated on the 6 human glioblastoma multiforme was similar to the value previously reported for 6 carcinoma cell lines and consistent with National Cancer Institute data, which also reveal a mean IC50 value of 47 nmol/L for the compound across a panel of 60 cancer cell lines [1].
Narciclasine is a toxic alkaloid found in various Amaryllidaceae species, modulatting the Rho/ROCK/LIM kinase/cofilin pathway, stimulating RhoA activation and inducing actin polymerization. The cytostatic activity of Narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. Thus, Narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases.
In vitro: In a MM46 cell in-vitro study, authors examined the inhibitory activities of Amaryllidaceae alkaloids, namely, lycoricidinol (narciclasine), hippeastrine and ungerine against the cytotoxicity of calprotectin. It was found that lycoricidinol (narciclasine) inhibited calprotectin-induced cytotoxicity at more than 10-fold lower concentration (IC50=0.001-0.01 μ/ml) than lycorine, while the effects of the latter two alkaloids were very weak [2].
In vivo: In an in-vivo study, the authors checked the prophylactic effect of lycorine and lycoricidinol (narciclasine) on the adjuvant arthritis model in rats. Results showed that lycoricidinol (narciclasine), rather than lycorine, significantly suppressed the degree of swelling of adjuvant-treated as well as untreated feet, suggesting that lycoricidinol (narciclasine) might be a candidate as a the drug having marked suppressive activity for inflammation which might be influenced by calprotectin [2].
Clinical trial: Up to now, Narciclasine is still in the preclinical development stage and are planned to move toward clinical trials in oncology within a 3-4 year period in order to help patients with brain cancers, including gliomas, as well as brain metastases, which was said by Robert Kiss, Ph.D., co-author of the study from the Laboratory of Toxicology at the Institute of Pharmacy at the Université Libre de Bruxelles in Brussels, Belgium.
Reference:
[1] Lefranc F, Sauvage S, Van Goietsenoven G, Mégalizzi V, Lamoral-Theys D, Debeir O, Spiegl-Kreinecker S, Berger W, Mathieu V, Decaestecker C, Kiss R. Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells. Mol Cancer Ther. 2009;8(7):1739-50.
[2] Mikami M, Kitahara M, Kitano M, Ariki Y, Mimaki Y, Sashida Y, Yamazaki M, Yui S. Suppressive activity of lycoricidinol (narciclasine) against cytotoxicity of neutrophil-derived calprotectin, and its suppressive effect on rat adjuvant arthritis model. Biol Pharm Bull. 1999;22(7):674-8.
Kinase experiment: | The RhoA G-LISA assay is used. The assay uses a 96-well plate coated with the Rho binding domain of Rho family effector proteins. The active GTP-bound form of the Rho family protein but not the inactive GDP-bound form from biological samples will bind to the plate. Bound active Rho family protein is then detected by incubation with a specific primary antibody followed by a secondary antibody conjugated to horseradish peroxidase. The signal is then developed using OPD. U373 and GL19 glioblastoma multiforme cells are serum starved for 24 h and left untreated or treated with Narciclasine (100 nM) for 3 min, 5 min, 30 min, 1 h, and 2 h or treated with 2.0 μg/mL of the cell-permeable Rho inhibitor for 4 h in serum-free medium at 37°C with and without subsequent Narciclasine treatment. This product consists of highly purified C3 transferase covalently linked to a proprietary cell-penetrating moiety via a disulfide bond. The cell-penetrating moiety allows rapid and efficient transport through the plasma membrane. Once in the cytosol, the cell-penetrating moiety is released, thereby allowing C3 transferase to freely diffuse intracellularly and inactive RhoA, RhoB, and RhoC but not related GTPases such as Cdc42 or Rac1. C3 transferase inhibits Rho proteins by ADP ribosylation on Asn41 in the effector binding domain of the GTPase. Cells are then lysed and RhoA activity is measured by the RhoA G-LISA Activation Assay or alternatively cells are stained for F-actin[1]. |
Cell experiment: | Cell[1]The Narciclasine IC50 concentration, the Narciclasine concentration that decreased by 50% the global growth rate of a given cell population, is assessed with the MTT assay. The cells are incubated for 72 h in the presence and absence of the Narciclasine (with concentrations ranging between 10-9 and 10-5 M concentrate) for the determination of Narciclasine IC50 values[1]. |
Animal experiment: | Mice[1] The Hs683 cell line and GL19 primoculture grafted into the brains of nude immunodeficient mice both produced invasive brain tumors. Xenograft-bearing mice receive vehicle alone, oral temozolomide at 40 mg/kg (5 administrations per week for 5 consecutive weeks), or Narciclasine at 1 mg/kg either oral (once per week for 5 weeks) or i.v. (twice per week for 5 weeks). Drug administration is initiated respectively on days 5 and 7 post-tumor grafting for the Hs683 and GL19 models. The temozolomide dose and treatment schedule are selected based on previous optimized regimens. Narciclasine dose and treatment schedule are selected based on Narciclasine toxicity study in rats after oral administration and pharmacokinetic study that we have recently published. In toxicity study, Narciclasine (25, 10, or 1 mg/kg) is administered five times a week for 3 weeks and the no adverse effect level dose is defined to be 1 mg/kg/d p.o., with minimal acanthosis reactive changes and minor variations in some biochemistry parameters observed at this dose level considered to be nonadverse. |
参考文献: [1]. Lefranc F, et al. Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells. Mol Cancer Ther. 2009 Jul;8(7):1739-50. | |
动态评分
0.0