title: Synergistic killing of human small cell lung cancer cells by the Bcl-2-inositol 1,4,5-trisphosphate receptor disruptor BIRD-2 and the BH3-mimetic ABT-263.
abstract: Small cell lung cancer (SCLC) has an annual mortality approaching that of breast and prostate cancer. Although sensitive to initial chemotherapy, SCLC rapidly develops resistance, leading to less effective second-line therapies. SCLC cells often overexpress Bcl-2, which protects cells from apoptosis both by sequestering pro-apoptotic family members and by modulating inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium signaling. BH3-mimetic agents such as ABT-263 disrupt the former activity but have limited activity in SCLC patients. Here we report for the first time that Bcl-2-IP3 receptor disruptor-2 (BIRD-2), a decoy peptide that binds to the BH4 domain of Bcl-2 and prevents Bcl-2 interaction with IP3Rs, induces cell death in a wide range of SCLC lines, including ABT-263-resistant lines. BIRD-2-induced death of SCLC cells appears to be a form of caspase-independent apoptosis mediated by calpain activation. By targeting different regions of the Bcl-2 protein and different mechanisms of action, BIRD-2 and ABT-263 induce cell death synergistically. Based on these findings, we propose that targeting the Bcl-2-IP3R interaction be pursued as a novel therapeutic strategy for SCLC, either by developing BIRD-2 itself as a therapeutic agent or by developing small-molecule inhibitors that mimic BIRD-2.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA.|Department of Medicine, MetroHealth Medical Center, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: Greenberg
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: McColl
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhong
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Wildey
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH, USA.|Case Comprehensive Cancer Center, Cleveland, OH, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Distelhorst
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology*; D055752:Small Cell Lung Carcinoma / Q000201:enzymology / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; C000609867:BIRD-2 peptide; D010455:Peptides; D013449:Sulfonamides; D002154:Calpain; D020169:Caspases; D002118:Calcium; C528561:navitoclax