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

Abstract

Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412.

• Authors: 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, James D Griffin
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 7 Pg. 1951-61 (Jul 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17620426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Carrier Proteins
• Diablo protein, mouse
• Inhibitor of Apoptosis Proteins
• LBW242
• Mitochondrial Proteins
• Mutant Proteins
• Oligopeptides
• Flt3 protein, mouse
• fms-Like Tyrosine Kinase 3
• Staurosporine
• midostaurin

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• Biomimetic Materials (pharmacology)
• Carrier Proteins
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Leukemia (drug therapy)
• Mice
• Mitochondrial Proteins
• Mutant Proteins (genetics, metabolism)
• Oligopeptides (chemistry, pharmacology)
• Staurosporine (analogs & derivatives, pharmacology)
• Stromal Cells (drug effects)
• fms-Like Tyrosine Kinase 3 (genetics, metabolism)