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Exp Cell Res ; 338(2): 251-60, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26302264

ABSTRACT

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Subject(s)
Antineoplastic Agents/pharmacology , Biological Transport/drug effects , Caspase 3/metabolism , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mitochondrial Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins , Biomimetics/methods , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Female , HCT116 Cells , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Melanoma/drug therapy , Melanoma/metabolism , Mice, Inbred BALB C , Mice, Nude , Protein Binding/drug effects , Protein Structure, Tertiary/drug effects
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