title: BCL-xL/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells.
abstract: The acute promyelocytic leukemia (APL) subtype of acute myeloid leukemia (AML) is characterized by chromosomal translocations that result in fusion proteins, including the promyelocytic leukemia-retinoic acid receptor, alpha fusion protein (PML-RARα). All-trans retinoic acid (atRA) treatment is the standard drug treatment for APL yielding cure rates > 80% by activating transcription and proteasomal degradation of retinoic acid receptor, alpha (RARα). Whereas combination therapy with As2O3 has increased survival further, patients that experience relapse and are refractory to atRA and/or As2O3 is a clinically significant problem. BCL-2 family proteins regulate apoptosis and over-expression of anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) family proteins has been associated with chemotherapeutic resistance in APL including impairment of the ability of atRA to induce growth arrest and differentiation. Here we investigated the novel BH3 domain mimetic, JY-1-106, which antagonizes the anti-apoptotic BCL-2 family members B-cell lymphoma-extra large (BCL-xL) and myeloid cell leukemia-1 (MCL-1) alone and in combination with retinoids including atRA, AM580 (RARα agonist), and SR11253 (RARγ antagonist). JY-1-106 reduced cell viability in HL-60 cells alone and in combination with retinoids. The combination of JY-1-106 and SR11253 had the greatest impact on cell viability by stimulating apoptosis. These studies indicate that dual BCL-xL/MCL-1 inhibitors and retinoids could work cooperatively in leukemia treatment.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Perri
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Yap
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA.
authors.forename: Jianshi
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, Ed. Polifunzionale, University of Calabria, 87036 Rende, CS, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Cione
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201, USA. Electronic address: mkane@rx.umaryland.edu.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000008:administration & dosage; D001565:Benzoates / Q000008:administration & dosage; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D014212:Tretinoin / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*; D062366:para-Aminobenzoates / Q000008:administration & dosage; D000097768:Retinoic Acid Receptor gamma
chemical_list: D001549:Benzamides; D001565:Benzoates; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; D014212:Tretinoin; D051020:bcl-X Protein; D062366:para-Aminobenzoates; D000097768:Retinoic Acid Receptor gamma; C494811:BCL2L1 protein, human; C587245:JY-1-106; C579095:MCL1 protein, human; C000607071:RARA protein, human; C068073:Am 580
keywords: Apoptosis; BCL-x(L); HL60; Leukemia; MCL-1; Retinoic acid
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