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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

KGI kills preferentially cancer cells over normal cells with no recovery of residual cells while BBE blocks the killing effect of KGI. A) KGI induces cell death in U937 monoblast cancer cells at about 30-fold lower concentration than that required to kill normal monocytes derived immature DCs (mDC) measured by Alamar Blue method and expressed as IC50. B) The U937 cancer cells were synchronized in cell cycle and then cultured with 2 μg/mL of KGI for the first three days. The viable cells were counted at indicated time points. Even after a prolonged culture for 12 days there was no residual cancer cells treated with KGI reverting to replication. C) U937 cells were exposed to a fixed concentration of KGI (77 μg/mL) and increasing concentrations of BBE (X axis). As shown, close to 100% blocking by BBE was achieved when the ratio between BBE and KGI approaching 10 to 1.
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f3-ijn-5-051: KGI kills preferentially cancer cells over normal cells with no recovery of residual cells while BBE blocks the killing effect of KGI. A) KGI induces cell death in U937 monoblast cancer cells at about 30-fold lower concentration than that required to kill normal monocytes derived immature DCs (mDC) measured by Alamar Blue method and expressed as IC50. B) The U937 cancer cells were synchronized in cell cycle and then cultured with 2 μg/mL of KGI for the first three days. The viable cells were counted at indicated time points. Even after a prolonged culture for 12 days there was no residual cancer cells treated with KGI reverting to replication. C) U937 cells were exposed to a fixed concentration of KGI (77 μg/mL) and increasing concentrations of BBE (X axis). As shown, close to 100% blocking by BBE was achieved when the ratio between BBE and KGI approaching 10 to 1.

Mentions: We selected the U937 cells to investigate the effects of KGI and BBE particles because of our background knowledge of tumor and normal cells of similar origin, ie, monocyte-derived immature dendritic cells (DCs). We compared the killing effects by KGI and BBE on cancer cells with that on the monocyte derived normal DCs. KGI killed U937 cells at a 30-fold lower concentration than was required to kill the normal DCs (Figure 3a). The effect on U937 cells was not reversible since the removal of the drug after three days did not allow cells to recover during the 12 days of culture. KGI at 2 μg/mL for three days reduced the cell number to 50% and eventually killed almost all tumor cells after 12 days of culture (Figure 3b), even 0.5 μg/mL of KGI caused continues repression of cancer cell growth during the 12 days of culture (data not shown). BBE did not induce cell death either in U937 or in normal DCs (Table 2). When a fixed concentration of 77 μg/mL KGI was mixed with increased concentrations of BBE, the killing effect of KGI was blocked in a concentration dependent manner. At a BBE:KGI ratio of 10:1, close to 100% blocking was observed (Figure 3c).


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)

KGI kills preferentially cancer cells over normal cells with no recovery of residual cells while BBE blocks the killing effect of KGI. A) KGI induces cell death in U937 monoblast cancer cells at about 30-fold lower concentration than that required to kill normal monocytes derived immature DCs (mDC) measured by Alamar Blue method and expressed as IC50. B) The U937 cancer cells were synchronized in cell cycle and then cultured with 2 μg/mL of KGI for the first three days. The viable cells were counted at indicated time points. Even after a prolonged culture for 12 days there was no residual cancer cells treated with KGI reverting to replication. C) U937 cells were exposed to a fixed concentration of KGI (77 μg/mL) and increasing concentrations of BBE (X axis). As shown, close to 100% blocking by BBE was achieved when the ratio between BBE and KGI approaching 10 to 1.
© Copyright Policy
Related In: Results  -  Collection

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

f3-ijn-5-051: KGI kills preferentially cancer cells over normal cells with no recovery of residual cells while BBE blocks the killing effect of KGI. A) KGI induces cell death in U937 monoblast cancer cells at about 30-fold lower concentration than that required to kill normal monocytes derived immature DCs (mDC) measured by Alamar Blue method and expressed as IC50. B) The U937 cancer cells were synchronized in cell cycle and then cultured with 2 μg/mL of KGI for the first three days. The viable cells were counted at indicated time points. Even after a prolonged culture for 12 days there was no residual cancer cells treated with KGI reverting to replication. C) U937 cells were exposed to a fixed concentration of KGI (77 μg/mL) and increasing concentrations of BBE (X axis). As shown, close to 100% blocking by BBE was achieved when the ratio between BBE and KGI approaching 10 to 1.
Mentions: We selected the U937 cells to investigate the effects of KGI and BBE particles because of our background knowledge of tumor and normal cells of similar origin, ie, monocyte-derived immature dendritic cells (DCs). We compared the killing effects by KGI and BBE on cancer cells with that on the monocyte derived normal DCs. KGI killed U937 cells at a 30-fold lower concentration than was required to kill the normal DCs (Figure 3a). The effect on U937 cells was not reversible since the removal of the drug after three days did not allow cells to recover during the 12 days of culture. KGI at 2 μg/mL for three days reduced the cell number to 50% and eventually killed almost all tumor cells after 12 days of culture (Figure 3b), even 0.5 μg/mL of KGI caused continues repression of cancer cell growth during the 12 days of culture (data not shown). BBE did not induce cell death either in U937 or in normal DCs (Table 2). When a fixed concentration of 77 μg/mL KGI was mixed with increased concentrations of BBE, the killing effect of KGI was blocked in a concentration dependent manner. At a BBE:KGI ratio of 10:1, close to 100% blocking was observed (Figure 3c).

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