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Molecular Cancer Therapeutics
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Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells

Ellen Weisberg, Andrew L. Kung, Renee D. Wright, Daisy Moreno, Laurie Catley, Arghya Ray, Leigh Zawel, Mary Tran, Jan Cools, Gary Gilliland, Constantine Mitsiades, Douglas W. McMillin, Jingrui Jiang, Elizabeth Hall-Meyers and James D. Griffin
Ellen Weisberg
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Andrew L. Kung
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Renee D. Wright
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Daisy Moreno
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Laurie Catley
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Arghya Ray
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Leigh Zawel
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Mary Tran
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Jan Cools
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Gary Gilliland
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Constantine Mitsiades
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Douglas W. McMillin
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Jingrui Jiang
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Elizabeth Hall-Meyers
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James D. Griffin
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DOI: 10.1158/1535-7163.MCT-06-0810 Published July 2007
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    Figure 1.

    Effects of LBW242 on proliferation of PKC412-sensitive and PKC412-resistant mutant FLT3-expressing cells. A, 2-d treatment of FLT3-ITD-Ba/F3 and PKC412-resistant Ba/F3-derived mutant FLT3 cells with PKC412 (n = 2). B, 3-d treatment of FLT3-ITD-Ba/F3 and PKC412-resistant Ba/F3-derived mutant FLT3 cells with LBW242 (n = 2). C, 3-d treatment of wild-type FLT3-Ba/F3 and D835Y-Ba/F3 cells with LBW242 (n = 2). D, IL-3 rescue of N676D-Ba/F3 cells treated in parallel for 2 d with LBW242 (n = 2) or PKC412 (n = 1). E, chemical structure of LBW242.

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    Figure 2.

    Effects of LBW242 plus PKC412 on proliferation of PKC412-sensitive and PKC412-resistant mutant FLT3-expressing cells. A, proliferation study showing 3-d treatments of FLT3-ITD-W51-Ba/F3 cells with PKC412, LBW242, or a combination of PKC412 and LBW242 (study shown is representative of three independent experiments). B, proliferation study showing 3-d treatments of A627T-Ba/F3 cells with PKC412, LBW242, or a combination of PKC412 and LBW242 (n = 1). C, proliferation study showing 3-d treatments of F691I-Ba/F3 cells with PKC412, LBW242, or a combination of PKC412 and LBW242 (n = 1). D, proliferation study showing 3-d treatments of G697R-Ba/F3 cells with PKC412, LBW242, or a combination of PKC412 and LBW242 (study shown is representative of two independent experiments).

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    Figure 3.

    Effects of LBW242 plus doxorubicin or Ara-c, respectively, on proliferation of PKC412-sensitive and PKC412-resistant mutant FLT3-expressing cells. A, proliferation study showing 3-d treatments of FLT3-ITD-Ba/F3 cells with doxorubicin, LBW242, or a combination of doxorubicin and LBW242 (n = 1). B, proliferation study showing 3-d treatments of A627T-Ba/F3 cells with doxorubicin, LBW242, or a combination of doxorubicin and LBW242 (n = 1). C, proliferation study showing 3-d treatments of FLT3-ITD-Ba/F3 cells with Ara-c, LBW242, or a combination of Ara-c and LBW242 (n = 1). D, proliferation study showing 3-d treatments of F691I-Ba/F3 cells with Ara-c, LBW242, or a combination of Ara-c and LBW242 (n = 1).

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    Figure 4.

    In vivo investigation of combined effects of PKC412 and LBW242. A–C, NCR nude mice injected with 800,000 Ba/F3-FLT3-ITD-luc+ cells via i.v. tail vein and then treated for up to 10 d by oral gavage with vehicle (NMP + PEG300), LBW242 (50 mg/kg) alone, PKC412 (40 mg/kg) alone, or a combination of LBW242 (50 mg/kg) and PKC412 (40 mg/kg). Mice were sacrificed 8 d after the last imaging day, spleen and total weights were measured, and mice were preserved in 10% formalin for histopathologic analysis. A, mouse photos show bioluminescence of mice following 7 d post-i.v. injection. B, bioluminescence, as shown in A, presented as percent baseline. C, percent spleen weights of mice treated for 10 d with LBW242, PKC412, or a combination of LBW242 and PKC412. D and E, NCR nude mice injected with 800,000 Ba/F3-FLT3-ITD-luc+ cells via i.v. tail vein and then treated for up to 6 d by oral gavage with vehicle (NMP + PEG300), LBW242 (50 mg/kg) alone, PKC412 (40 mg/kg) alone, or a combination of LBW242 (50 mg/kg) and PKC412 (40 mg/kg). Mice were sacrificed on the last imaging day (day 7 post-i.v. injection) and preserved in 10% formalin for histopathologic analysis. D, mouse photos show bioluminescence of mice following 7 d post-i.v. injection. E, bioluminescence, as shown in D, presented as percent baseline.

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    Figure 5.

    Effects of LBW242 plus PKC412 on stromal-mediated chemoresistance of FLT3-ITD-Ba/F3 cells. A, treatment of MOLM13-luc+ cells with different concentrations of PKC412 in the absence and the presence of the human stromal cell line, HS-5. B, PKC412 + LBW242 combination experiment using MOLM13-luc+ cells in the absence of stroma (top) and the presence of stroma (bottom).

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  • Table 1.

    Combination indices calculated for dose-response curves for combination studies described in results and shown in Figs. 2 and 3

    Cell linesCombination indices
    ED50ED76ED90
    FLT3-ITD-Ba/F3 (LBW242 + PKC412)0.747800.588080.47158
    A627T-Ba/F3 (LBW242 + PKC412)0555820.409460.36244
    F691l-Ba/F3 (LBW242 + PKC412)0.634090.432670.30145
    G697r-Ba/F3 (LBW242 + PKC412)0.397830.432100.47464
    FLT3-ITD-Ba/F3 (LBW242 + doxorubicin)0.897230.812950.73688
    A627T-Ba/F3 (LBW242 + doxorubicin)0.386130.356380.35964
    FLT3-ITD-Ba/F3 (LBW242 + Ara-c)0.607840.451490.33535
    F691l-Ba/F3 (LBW242 + Ara-c)0.603770.470240.41785

Additional Files

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    Files in this Data Supplement:

    • Supplementary Fig. S1
    • Supplementary Table S1
    • Supplementary Fig. S2
    • Supplementary Fig. S3
    • Supplementary Fig. S4
    • Supplementary Fig. S5
    • Supplementary Fig. S6
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    • Supplementary Fig. S8
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Molecular Cancer Therapeutics: 6 (7)
July 2007
Volume 6, Issue 7
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Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Ellen Weisberg, Andrew L. Kung, Renee D. Wright, Daisy Moreno, Laurie Catley, Arghya Ray, Leigh Zawel, Mary Tran, Jan Cools, Gary Gilliland, Constantine Mitsiades, Douglas W. McMillin, Jingrui Jiang, Elizabeth Hall-Meyers and James D. Griffin
Mol Cancer Ther July 1 2007 (6) (7) 1951-1961; DOI: 10.1158/1535-7163.MCT-06-0810

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Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Ellen Weisberg, Andrew L. Kung, Renee D. Wright, Daisy Moreno, Laurie Catley, Arghya Ray, Leigh Zawel, Mary Tran, Jan Cools, Gary Gilliland, Constantine Mitsiades, Douglas W. McMillin, Jingrui Jiang, Elizabeth Hall-Meyers and James D. Griffin
Mol Cancer Ther July 1 2007 (6) (7) 1951-1961; DOI: 10.1158/1535-7163.MCT-06-0810
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