title: A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2.
abstract: Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton's tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction.
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Andrew R
authors: AR
authors: Lavik
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Fei
authors: F
authors: Zhong
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Ming-Jin
authors: MJ
authors: Chang
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.|Department of Medicine, MetroHealth Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors: Edward
authors: E
authors: Greenberg
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Yuvraj
authors: Y
authors: Choudhary
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.|Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors: Mitchell R
authors: MR
authors: Smith
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Karen S
authors: KS
authors: McColl
authors: Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors: John
authors: J
authors: Pink
authors: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.|Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors: Frederic J
authors: FJ
authors: Reu
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.|Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors: Shigemi
authors: S
authors: Matsuyama
authors: Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.|Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
authors: Clark W
authors: CW
authors: Distelhorst
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007150:Immunohistochemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; C000609867:BIRD-2 peptide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C579720:venetoclax; C528561:navitoclax
keywords: ABT-199; Bcl-2; Bruton's tyrosine kinase; inositol 1,4,5-trisphosphate receptor; lymphoid malignancy