title: An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL.
abstract: Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL-specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2 gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: Yun
authors.initials: Y
authors.lastname: Mai
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: J Jessica
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: Boris
authors.initials: B
authors.lastname: Bartholdy
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Pediatrics.|The Children's Hospital at Montefiore.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Knapp
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: Fei
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: B Belinda
authors.initials: BB
authors.lastname: Ding
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Nuclear Medicine, and.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ken He
authors.initials: KH
authors.lastname: Young
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.|Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: Samir
authors.initials: S
authors.lastname: Parekh
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, NY.
authors.forename: B Hilda
authors.identifier: 0000-0002-2281-422X
authors.initials: BH
authors.lastname: Ye
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017606:Chlorine Compounds / Q000494:pharmacology; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D018858:Germinal Center / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D017671:Platinum Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D017606:Chlorine Compounds; D017671:Platinum Compounds; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; C529200:trichloronitritodiammineplatinum(IV); D004317:Doxorubicin