Narciclasine (Lycoricidinol), a natural product, modulates the Rho/Rho-kinase/LIM kinase/cofilin signaling pathway, greatly increasing GTPase RhoA activity.

Narciclasine activates Rho and stress fibers in glioblastoma multiforme cells (mean IC50: ~50 nM on the 6 human glioblastoma multiforme). It has a mean IC50 value of 47 nM across a panel of 60 cancer cell lines [1], and the IC50 for radicle growth inhibition is 0.1 μM for Narciclasine [2].

Intravenous (i.v.) administration of Narciclasine at 1 mg/kg significantly increases the survival of GL19 glioblastoma multiforme-bearing mice. Oral administration at the same dose, five times a week for 5 consecutive weeks, similarly enhances survival in this model. Oral treatment with Narciclasine at 1 mg/kg also significantly increases the survival of Hs683 glioblastoma multiforme-bearing mice. However, increasing the frequency of doses per week does not further improve survival in Hs683 glioblastoma multiforme-bearing mice [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 1 and 10000 nM concentrate) for the determination of Narciclasine IC50 values [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 graftings for the Hs683 and GL19 models. The temozolomide dose and treatment schedule are selected based on previously 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 [1].