39 research outputs found
Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells
BACKGROUND: With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma – an embryonal tumor with biological similarities to MB – the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression. METHODS: To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed. RESULTS: NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml) and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary. CONCLUSION: In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit proliferation of human MB cells in vivo
Polymeric Curcumin Nanoparticle Pharmacokinetics and Metabolism in Bile Duct Cannulated Rats
The
objective of this study was to compare the pharmacokinetics
and metabolism of polymeric nanoparticle-encapsulated (nanocurcumin)
and solvent-solubilized curcumin formulations in Sprague–Dawley
(SD) rats. Nanocurcumin is currently under development for cancer
therapy. Since free, unencapsulated curcumin is rapidly metabolized
and excreted in rats, upon intravenous (i.v.) administration of nanocurcumin
only nanoparticle-encapsulated curcumin can be detected in plasma
samples. Hence, the second objective of this study was to utilize
the metabolic instability of curcumin to assess <i>in vivo</i> drug release from nanocurcumin. Nanocurcumin and solvent-solubilized
curcumin were administered at 10 mg curcumin/kg by jugular vein to
bile duct-cannulated male SD rats (<i>n</i> = 5). Nanocurcumin
increased the plasma <i>C</i><sub>max</sub> of curcumin
1749 fold relative to the solvent-solubilized curcumin. Nanocurcumin
also increased the relative abundance of curcumin and glucuronides
in bile but did not dramatically alter urine and tissue metabolite
profiles. The observed increase in biliary and urinary excretion of
both curcumin and metabolites for the nanocurcumin formulation suggested
a rapid “burst” release of curcumin. Although the burst
release observed in this study is a limitation for targeted tumor
delivery, nanocurcumin still exhibits major advantages over solvent-solubilized
curcumin, as the nanoformulation does not result in the lung accumulation
observed for the solvent-solubilized curcumin and increases overall
systemic curcumin exposure. Additionally, the remaining encapsulated
curcumin fraction following burst release is available for tumor delivery
via the enhanced permeation and retention effect commonly observed
for nanoparticle formulations