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Nanoparticulate Quillaja saponin induces apoptosis in human leukemia cell lines with a high therapeutic index.

Hu K, Berenjian S, Larsson R, Gullbo J, Nygren P, Lövgren T, Morein B - Int J Nanomedicine (2010)

Bottom Line: The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol.The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner.In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences, Section of Virology, Uppsala University, Uppsala, Sweden.

ABSTRACT
Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol. Two fractions of QS were selected for particle formation, one with an acyl-chain (ASAP) was used to form killing and growth-inhibiting (KGI) particles, and the other without the acyl-chain (DSAP) was used to formulate blocking and balancing effect (BBE) particles. KGI showed significant growth inhibiting and cancer cell-killing activities in nine of 10 cell lines while BBE showed that on one cell line. The monoblastoid lymphoma cell line U937 was selected for analyzing the mode of action. Low concentrations of KGI (0.5 and 2 microg/mL) induced irreversible exit from the cell cycle, differentiation measured by cytokine production, and eventually programmed cell death (apoptosis). Compared to normal human monocytes, the U937 cells were 30-fold more sensitive to KGI. The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner. In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.

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Related in: MedlinePlus

Selected Quillaja saponin (QS) fractions, and their particulate forms. A) Reversed phase chromatography profile of QS. Fraction A (desacyl-saponin, DSAP) is the least hydrophobic QS fraction being the active saponin component in BBE particles. Fraction B (acyl-saponin, ASAP) is the most hydrophobic QS fraction being the active component in KGI particles. B) The triterpenoid structure of QS. The core is a triterpenoid with two carbohydrate chains in the position 3 and 18 and an acyl chain terminated with arabinose and rhamnose monosaccharides demarked with a ring in the Figure. C) Electron microscopic picture of KGI. BBE shows the same morphology. The diameter of the spheres is about 40 nm.
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f1-ijn-5-051: Selected Quillaja saponin (QS) fractions, and their particulate forms. A) Reversed phase chromatography profile of QS. Fraction A (desacyl-saponin, DSAP) is the least hydrophobic QS fraction being the active saponin component in BBE particles. Fraction B (acyl-saponin, ASAP) is the most hydrophobic QS fraction being the active component in KGI particles. B) The triterpenoid structure of QS. The core is a triterpenoid with two carbohydrate chains in the position 3 and 18 and an acyl chain terminated with arabinose and rhamnose monosaccharides demarked with a ring in the Figure. C) Electron microscopic picture of KGI. BBE shows the same morphology. The diameter of the spheres is about 40 nm.

Mentions: Purified QS fractions, the acyl-saponin (ASAP) and its particulate form KGI and the desacyl-saponin (DSAP) and its particulate form BBE (Figures 1a and 1b), were kindly supplied by Dr Karin Lövgren-Bengtsson (Isconova AB). These fractions are well characterized and used in commercial and experimental vaccine adjuvant formulations.11,13 The KGI and BBE particles were prepared as described previously.13 Briefly, to 0.05 mL of lipid mixture containing 10 mg/mL each of cholesterol (C) and phosphatidylcholine (PC), 0.025 mL of ASAP/DSAP solution (100 mg/mL) and 0.05 mL of phosphate-buffered saline (PBS) was added, mixed well and incubated at room temperature overnight. Then the mixture was dialyzed against PBS at room temperature for three days with changing PBS every 12 hours. The particles were purified through a 10% sucrose cushion overnight at 50.000 rpm 10 °C in a SW50.1 rotor followed by re-suspension in PBS overnight.


Nanoparticulate Quillaja saponin induces apoptosis in human leukemia cell lines with a high therapeutic index.

Hu K, Berenjian S, Larsson R, Gullbo J, Nygren P, Lövgren T, Morein B - Int J Nanomedicine (2010)

Selected Quillaja saponin (QS) fractions, and their particulate forms. A) Reversed phase chromatography profile of QS. Fraction A (desacyl-saponin, DSAP) is the least hydrophobic QS fraction being the active saponin component in BBE particles. Fraction B (acyl-saponin, ASAP) is the most hydrophobic QS fraction being the active component in KGI particles. B) The triterpenoid structure of QS. The core is a triterpenoid with two carbohydrate chains in the position 3 and 18 and an acyl chain terminated with arabinose and rhamnose monosaccharides demarked with a ring in the Figure. C) Electron microscopic picture of KGI. BBE shows the same morphology. The diameter of the spheres is about 40 nm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2819906&req=5

f1-ijn-5-051: Selected Quillaja saponin (QS) fractions, and their particulate forms. A) Reversed phase chromatography profile of QS. Fraction A (desacyl-saponin, DSAP) is the least hydrophobic QS fraction being the active saponin component in BBE particles. Fraction B (acyl-saponin, ASAP) is the most hydrophobic QS fraction being the active component in KGI particles. B) The triterpenoid structure of QS. The core is a triterpenoid with two carbohydrate chains in the position 3 and 18 and an acyl chain terminated with arabinose and rhamnose monosaccharides demarked with a ring in the Figure. C) Electron microscopic picture of KGI. BBE shows the same morphology. The diameter of the spheres is about 40 nm.
Mentions: Purified QS fractions, the acyl-saponin (ASAP) and its particulate form KGI and the desacyl-saponin (DSAP) and its particulate form BBE (Figures 1a and 1b), were kindly supplied by Dr Karin Lövgren-Bengtsson (Isconova AB). These fractions are well characterized and used in commercial and experimental vaccine adjuvant formulations.11,13 The KGI and BBE particles were prepared as described previously.13 Briefly, to 0.05 mL of lipid mixture containing 10 mg/mL each of cholesterol (C) and phosphatidylcholine (PC), 0.025 mL of ASAP/DSAP solution (100 mg/mL) and 0.05 mL of phosphate-buffered saline (PBS) was added, mixed well and incubated at room temperature overnight. Then the mixture was dialyzed against PBS at room temperature for three days with changing PBS every 12 hours. The particles were purified through a 10% sucrose cushion overnight at 50.000 rpm 10 °C in a SW50.1 rotor followed by re-suspension in PBS overnight.

Bottom Line: The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol.The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner.In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Sciences, Section of Virology, Uppsala University, Uppsala, Sweden.

ABSTRACT
Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol. Two fractions of QS were selected for particle formation, one with an acyl-chain (ASAP) was used to form killing and growth-inhibiting (KGI) particles, and the other without the acyl-chain (DSAP) was used to formulate blocking and balancing effect (BBE) particles. KGI showed significant growth inhibiting and cancer cell-killing activities in nine of 10 cell lines while BBE showed that on one cell line. The monoblastoid lymphoma cell line U937 was selected for analyzing the mode of action. Low concentrations of KGI (0.5 and 2 microg/mL) induced irreversible exit from the cell cycle, differentiation measured by cytokine production, and eventually programmed cell death (apoptosis). Compared to normal human monocytes, the U937 cells were 30-fold more sensitive to KGI. The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner. In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.

Show MeSH
Related in: MedlinePlus