Panobinostat enhances cytarabine and daunorubicin sensitivities in AML cells through suppressing the expression of BRCA1, CHK1, and Rad51.
Acute myeloid leukemia (AML) remains a challenging disease to treat and urgently requires new therapies to improve its treatment outcome. In this study, we investigated the molecular mechanisms underlying the cooperative antileukemic activities of panobinostat and cytarabine or daunorubicin (DNR) in AML cell lines and diagnostic blast samples in vitro and in vivo. Panobinostat suppressed expression of BRCA1, CHK1, and RAD51 in AML cells in a dose-dependent manner. Further, panobinostat significantly increased cytarabine- or DNR-induced DNA double-strand breaks and apoptosis, and abrogated S and/or G2/M cell cycle checkpoints. Analogous results were obtained by shRNA knockdown of BRCA1, CHK1, or RAD51. Cotreatment of NOD-SCID-IL2Rγ(null) mice bearing AML xenografts with panobinostat and cytarabine significantly increased survival compared to either cytarabine or panobinostat treatment alone. Additional studies revealed that panobinostat suppressed the expression of BRCA1, CHK1, and RAD51 through downregulation of E2F1 transcription factor. Our results establish a novel mechanism underlying the cooperative antileukemic activities of these drug combinations in which panobinostat suppresses expression of BRCA1, CHK1, and RAD51 to enhance cytarabine and daunorubicin sensitivities in AML cells.
Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, United States of America ; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, United States of America ; The State Engineering Laboratory of AIDS Vaccine, College of Life Science, Jilin University, Changchun, China.
Chengzhi
C
Xie
Christina
C
Drenberg
Holly
H
Edwards
J Timothy
JT
Caldwell
Wei
W
Chen
Hiroto
H
Inaba
Xuelian
X
Xu
Steven A
SA
Buck
Jeffrey W
JW
Taub
Sharyn D
SD
Baker
Yubin
Y
Ge
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000096:biosynthesis*; D000071877:Checkpoint Kinase 1; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000494:pharmacology*; D003630:Daunorubicin / Q000819:agonists / Q000494:pharmacology*; D054313:Drug Agonism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D000077767:Panobinostat; D011494:Protein Kinases / Q000096:biosynthesis*; D051135:Rad51 Recombinase / Q000096:biosynthesis*; D020298:U937 Cells
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D006877:Hydroxamic Acids; D007211:Indoles; D003561:Cytarabine; D000077767:Panobinostat; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D003630:Daunorubicin