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Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.

Amit-Vazina M, Shishodia S, Harris D, Van Q, Wang M, Weber D, Alexanian R, Talpaz M, Aggarwal BB, Estrov Z - Br. J. Cancer (2005)

Bottom Line: Multiple myeloma (MM) accounts for 1 % of all cancer deaths.Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase.These data suggest that Atiprimod has a role in future therapies for MM.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod (2-(3-Diethylaminopropyl)-8,8-dipropyl-2-azaspiro[4,5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a time- and dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G(0)/G(1) phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

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Effect of Atiprimod on the cell cycle status of U266-B1 cells. These cells were incubated in RPMI 1640 supplemented with 10% FCS with or without 6 μM Atiprimod, and cell cycle analysis was performed as described above. The percentages of cells in sub-G0, G0/G1, S, and G2M phases of the cell cycle are given.
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fig4: Effect of Atiprimod on the cell cycle status of U266-B1 cells. These cells were incubated in RPMI 1640 supplemented with 10% FCS with or without 6 μM Atiprimod, and cell cycle analysis was performed as described above. The percentages of cells in sub-G0, G0/G1, S, and G2M phases of the cell cycle are given.

Mentions: As Atiprimod blocked STAT3 phosphorylation and inhibited MM cell proliferation, we asked how this drug affects the progression of U266-B1 cells through the cell cycle. To answer this question, we incubated U266-B1 cells with 6 μM Atiprimod and performed a cell cycle analysis using flow cytometry. We found that Atiprimod induced a sub-G0/G1accumulation with 44.3 and 52.2% of the cells accumulating in sub-G0 phase at 60 and 90 min, respectively (Figure 4).


Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.

Amit-Vazina M, Shishodia S, Harris D, Van Q, Wang M, Weber D, Alexanian R, Talpaz M, Aggarwal BB, Estrov Z - Br. J. Cancer (2005)

Effect of Atiprimod on the cell cycle status of U266-B1 cells. These cells were incubated in RPMI 1640 supplemented with 10% FCS with or without 6 μM Atiprimod, and cell cycle analysis was performed as described above. The percentages of cells in sub-G0, G0/G1, S, and G2M phases of the cell cycle are given.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361492&req=5

fig4: Effect of Atiprimod on the cell cycle status of U266-B1 cells. These cells were incubated in RPMI 1640 supplemented with 10% FCS with or without 6 μM Atiprimod, and cell cycle analysis was performed as described above. The percentages of cells in sub-G0, G0/G1, S, and G2M phases of the cell cycle are given.
Mentions: As Atiprimod blocked STAT3 phosphorylation and inhibited MM cell proliferation, we asked how this drug affects the progression of U266-B1 cells through the cell cycle. To answer this question, we incubated U266-B1 cells with 6 μM Atiprimod and performed a cell cycle analysis using flow cytometry. We found that Atiprimod induced a sub-G0/G1accumulation with 44.3 and 52.2% of the cells accumulating in sub-G0 phase at 60 and 90 min, respectively (Figure 4).

Bottom Line: Multiple myeloma (MM) accounts for 1 % of all cancer deaths.Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase.These data suggest that Atiprimod has a role in future therapies for MM.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod (2-(3-Diethylaminopropyl)-8,8-dipropyl-2-azaspiro[4,5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a time- and dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G(0)/G(1) phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

Show MeSH
Related in: MedlinePlus