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Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor.

Jurczyszyn A, Zebzda A, Czepiel J, Perucki W, Bazan-Socha S, Cibor D, Owczarek D, Majka M - J Cancer (2014)

Bottom Line: The first significant effects of GA on U266 cells was observed after 24 hours.In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities.Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Hematology, Jagiellonian University Medical College, Krakow, Poland.

ABSTRACT
Introduction. Geldanamycin (GA) is an ansamycin antibiotic that exhibits potent anti-neoplastic properties. The aim of this study was to assess the impact of GA and its derivatives on the growth and invasiveness of myeloma cell lines and CD138+ cells derived from the bone marrow of patients with multiple myeloma. Materials and methods. We evaluated cell proliferation, survival, apoptosis, cell cycle of myeloma cells, and the expression of cell surface proteins after incubation with geldanamycin or its derivatives. Results. GA and its analogs have an effect on myeloma cells by inhibiting their growth in a time and dose-dependent manner. Myeloma cell lines demonstrated decreased proliferation after incubation with 10 nM of GA or 100 nM GA analogs. The first significant effects of GA on U266 cells was observed after 24 hours. After 24 hours, U266 cells incubated with 100 nM GA were in both early and late stages of apoptosis; 17AEP and 17DMAG caused apoptosis of similar intensity to GA. It has been observed that GA and its derivatives cause caspase-3 activation. Analysis of the activity of AKT and MAP 42/44 kinases was performed by incubating U266 cells for 24 and 48 hours in100 nM of GA and its derivatives. After 24 hours incubation, no significant changes in protein expression were observed, while after 48 hours, the strongest changes were seen in AKT protein expression after incubation with GA and 17AEP-GA. In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities. We observed a nearly two-fold increase in U266 cells in the G1 phase and a simultaneous decrease in the percentage of cells in the G2/M phase, indicating that cells were halted in the G1 phase. In the case of the INA6 cells, proliferation was halted in both the G1 and G2/M phases. Conclusions. GA and the analogues that we tested can inhibit myeloma cell growth by induction of apoptosis and blockage of cell cycle progression, and have an effect on the down-regulation of the MET receptor. The GA derivatives tested, despite their modifications still retain strong anticancer properties. Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.

No MeSH data available.


Related in: MedlinePlus

Effects of GA and its derivatives on the expression of AKT and MAP. 1-control, 2-GA, 3-17AEP-GA, 4-17DMAP-GA, 5-17AAG, 6-17DMAG.GAPDH-control constitutive protein.
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Figure 7: Effects of GA and its derivatives on the expression of AKT and MAP. 1-control, 2-GA, 3-17AEP-GA, 4-17DMAP-GA, 5-17AAG, 6-17DMAG.GAPDH-control constitutive protein.

Mentions: Among the many cellular proteins, regulatory proteins play a very important role in the regulation of the controlled process of death. Three independent experiments were conducted examining the levels of AKT kinase, one of the key proteins that control the process of apoptosis, and MAP 42/44 which has an influence on gene expression, cellular division, cellular differentiation, cellular movement, and apoptosis. Analysis of the activity of AKT kinase and MAP 42/44 were made by incubating U266 cells for 24 and 48 hours with 100 nM of GA and its derivatives. After 24 hours incubation, there were no significant changes in protein expression (data not shown), while after 48 hours the strongest effects was seen in expression of the AKT protein when incubated with GA or 17AEP-GA (Fig. 7). The strongest effects were observed after incubation with GA, 17AEP-GA, and 17DMAG.


Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor.

Jurczyszyn A, Zebzda A, Czepiel J, Perucki W, Bazan-Socha S, Cibor D, Owczarek D, Majka M - J Cancer (2014)

Effects of GA and its derivatives on the expression of AKT and MAP. 1-control, 2-GA, 3-17AEP-GA, 4-17DMAP-GA, 5-17AAG, 6-17DMAG.GAPDH-control constitutive protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4066360&req=5

Figure 7: Effects of GA and its derivatives on the expression of AKT and MAP. 1-control, 2-GA, 3-17AEP-GA, 4-17DMAP-GA, 5-17AAG, 6-17DMAG.GAPDH-control constitutive protein.
Mentions: Among the many cellular proteins, regulatory proteins play a very important role in the regulation of the controlled process of death. Three independent experiments were conducted examining the levels of AKT kinase, one of the key proteins that control the process of apoptosis, and MAP 42/44 which has an influence on gene expression, cellular division, cellular differentiation, cellular movement, and apoptosis. Analysis of the activity of AKT kinase and MAP 42/44 were made by incubating U266 cells for 24 and 48 hours with 100 nM of GA and its derivatives. After 24 hours incubation, there were no significant changes in protein expression (data not shown), while after 48 hours the strongest effects was seen in expression of the AKT protein when incubated with GA or 17AEP-GA (Fig. 7). The strongest effects were observed after incubation with GA, 17AEP-GA, and 17DMAG.

Bottom Line: The first significant effects of GA on U266 cells was observed after 24 hours.In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities.Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Hematology, Jagiellonian University Medical College, Krakow, Poland.

ABSTRACT
Introduction. Geldanamycin (GA) is an ansamycin antibiotic that exhibits potent anti-neoplastic properties. The aim of this study was to assess the impact of GA and its derivatives on the growth and invasiveness of myeloma cell lines and CD138+ cells derived from the bone marrow of patients with multiple myeloma. Materials and methods. We evaluated cell proliferation, survival, apoptosis, cell cycle of myeloma cells, and the expression of cell surface proteins after incubation with geldanamycin or its derivatives. Results. GA and its analogs have an effect on myeloma cells by inhibiting their growth in a time and dose-dependent manner. Myeloma cell lines demonstrated decreased proliferation after incubation with 10 nM of GA or 100 nM GA analogs. The first significant effects of GA on U266 cells was observed after 24 hours. After 24 hours, U266 cells incubated with 100 nM GA were in both early and late stages of apoptosis; 17AEP and 17DMAG caused apoptosis of similar intensity to GA. It has been observed that GA and its derivatives cause caspase-3 activation. Analysis of the activity of AKT and MAP 42/44 kinases was performed by incubating U266 cells for 24 and 48 hours in100 nM of GA and its derivatives. After 24 hours incubation, no significant changes in protein expression were observed, while after 48 hours, the strongest changes were seen in AKT protein expression after incubation with GA and 17AEP-GA. In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities. We observed a nearly two-fold increase in U266 cells in the G1 phase and a simultaneous decrease in the percentage of cells in the G2/M phase, indicating that cells were halted in the G1 phase. In the case of the INA6 cells, proliferation was halted in both the G1 and G2/M phases. Conclusions. GA and the analogues that we tested can inhibit myeloma cell growth by induction of apoptosis and blockage of cell cycle progression, and have an effect on the down-regulation of the MET receptor. The GA derivatives tested, despite their modifications still retain strong anticancer properties. Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.

No MeSH data available.


Related in: MedlinePlus