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The effects of forodesine in murine and human multiple myeloma cells.

Bieghs L, Caers J, De Bruyne E, Van Valckenborgh E, Higginbotham F, Vanderkerken K, Menu E - Adv Hematol (2010)

Bottom Line: Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels.We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis.We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.

ABSTRACT
Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, characterized by a monoclonal proliferation of malignant cells in the bone marrow. Despite recent advances in treatment strategies, MM remains incurable and new therapeutical targets are needed. Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels. We therefore tested whether forodesine was able to inhibit proliferation and/or induce apoptosis in both murine and human MM cells through a similar pathway. We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis. When investigating the pathways leading to cell cycle arrest and apoptosis, we observed an upregulation of p27, caspase 3, and BIM. We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells. Forodesine might be however potentiating towards other established cytotoxic drugs in MM.

No MeSH data available.


Related in: MedlinePlus

Effect of forodesine on proliferation of MM cells. The relative amount of BrdU uptake is shown in MOLT-4, 5T33MM, and RPMI-8226 cells treated with different concentrations of forodesine and dGuo at 24 hours (a, b, c) and 48 hours (d, e, f). The mean value + SD is shown of 3 independent experiments; *P < .05 compared to CT, CT = control, and FD = forodesine.
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fig3: Effect of forodesine on proliferation of MM cells. The relative amount of BrdU uptake is shown in MOLT-4, 5T33MM, and RPMI-8226 cells treated with different concentrations of forodesine and dGuo at 24 hours (a, b, c) and 48 hours (d, e, f). The mean value + SD is shown of 3 independent experiments; *P < .05 compared to CT, CT = control, and FD = forodesine.

Mentions: As we observed some increase in dGTP levels in the MM cells we continued to examine the effects of forodesine on the proliferation and apoptosis of the cells. We now used different concentrations of forodesine together with different concentrations of dGuo for 24 and 48 hours. At 24 hours we saw some reduction in BrdU uptake in both MOLT-4 (Figure 3(a)) and RPMI-8226 (Figure 3(c)) cells (up to 40% reduction) but not in the 5T33MM cells (Figure 3(b)). When looking at the effects at 48 hours, we found a complete block in proliferation in the MOLT-4 cells (Figure 3(d)) and 15% reduction in the 5T33MM cells (Figure 3(e)). Examination of the number of apoptotic cells revealed that forodesine had no effect on the MM cells at 24 hours (Figures 4(b) and 4(c)), while it did reduce the percentage of living cells in the MOLT-4 cells with 40% (Figure 4(a)). At 48 hours we saw in the MOLT-4 cells a pronounced dose-dependent decrease of the living cells when treated with different concentrations of dGuo, while the concentration of forodesine made no difference (Figure 4(d)). Here also a decrease in living cells could be seen when 20 μM and 30 μM dGuo were added alone, correlating to the observed increase in dGTP levels. In the MM cells we observed no (5T33MM) or small (10%, RPMI-8226) effect of forodesine treatment (Figures 4(e) and 4(f)). When the 5T33MMvv cells were treated ex vivo with forodesine, we also found a limited effect (up to 20%, data not shown).


The effects of forodesine in murine and human multiple myeloma cells.

Bieghs L, Caers J, De Bruyne E, Van Valckenborgh E, Higginbotham F, Vanderkerken K, Menu E - Adv Hematol (2010)

Effect of forodesine on proliferation of MM cells. The relative amount of BrdU uptake is shown in MOLT-4, 5T33MM, and RPMI-8226 cells treated with different concentrations of forodesine and dGuo at 24 hours (a, b, c) and 48 hours (d, e, f). The mean value + SD is shown of 3 independent experiments; *P < .05 compared to CT, CT = control, and FD = forodesine.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963119&req=5

fig3: Effect of forodesine on proliferation of MM cells. The relative amount of BrdU uptake is shown in MOLT-4, 5T33MM, and RPMI-8226 cells treated with different concentrations of forodesine and dGuo at 24 hours (a, b, c) and 48 hours (d, e, f). The mean value + SD is shown of 3 independent experiments; *P < .05 compared to CT, CT = control, and FD = forodesine.
Mentions: As we observed some increase in dGTP levels in the MM cells we continued to examine the effects of forodesine on the proliferation and apoptosis of the cells. We now used different concentrations of forodesine together with different concentrations of dGuo for 24 and 48 hours. At 24 hours we saw some reduction in BrdU uptake in both MOLT-4 (Figure 3(a)) and RPMI-8226 (Figure 3(c)) cells (up to 40% reduction) but not in the 5T33MM cells (Figure 3(b)). When looking at the effects at 48 hours, we found a complete block in proliferation in the MOLT-4 cells (Figure 3(d)) and 15% reduction in the 5T33MM cells (Figure 3(e)). Examination of the number of apoptotic cells revealed that forodesine had no effect on the MM cells at 24 hours (Figures 4(b) and 4(c)), while it did reduce the percentage of living cells in the MOLT-4 cells with 40% (Figure 4(a)). At 48 hours we saw in the MOLT-4 cells a pronounced dose-dependent decrease of the living cells when treated with different concentrations of dGuo, while the concentration of forodesine made no difference (Figure 4(d)). Here also a decrease in living cells could be seen when 20 μM and 30 μM dGuo were added alone, correlating to the observed increase in dGTP levels. In the MM cells we observed no (5T33MM) or small (10%, RPMI-8226) effect of forodesine treatment (Figures 4(e) and 4(f)). When the 5T33MMvv cells were treated ex vivo with forodesine, we also found a limited effect (up to 20%, data not shown).

Bottom Line: Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels.We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis.We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.

ABSTRACT
Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, characterized by a monoclonal proliferation of malignant cells in the bone marrow. Despite recent advances in treatment strategies, MM remains incurable and new therapeutical targets are needed. Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels. We therefore tested whether forodesine was able to inhibit proliferation and/or induce apoptosis in both murine and human MM cells through a similar pathway. We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis. When investigating the pathways leading to cell cycle arrest and apoptosis, we observed an upregulation of p27, caspase 3, and BIM. We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells. Forodesine might be however potentiating towards other established cytotoxic drugs in MM.

No MeSH data available.


Related in: MedlinePlus