An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL

Yun Mai, J. Jessica Yu, Boris A. Bartholdy, Zijun Y. Xu-Monette, Esther E. Knapp, Fei Yuan, Hongshan Chen, B. Belinda Ding, Zhihua Yao, Bhaskar Das, Yiyu Zou, Ken He Young, Samir Parekh, B. Hilda Ye

Research output: Contribution to journalArticle

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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 smallmolecule 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.

Original languageEnglish (US)
Pages (from-to)2797-2807
Number of pages11
JournalBlood
Volume128
Issue number24
DOIs
StatePublished - Dec 15 2016

Fingerprint

Oxidative stress
Lymphoma, Large B-Cell, Diffuse
Cytotoxicity
Doxorubicin
Oxidative Stress
B-Lymphocytes
Cells
Genes
Germinal Center
Therapeutics
DNA
Vincristine
Prednisone
Cyclophosphamide
Antioxidants
Oxidation-Reduction
DNA Damage
Cytoplasm
Homeostasis
Up-Regulation

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL. / Mai, Yun; Yu, J. Jessica; Bartholdy, Boris A.; Xu-Monette, Zijun Y.; Knapp, Esther E.; Yuan, Fei; Chen, Hongshan; Ding, B. Belinda; Yao, Zhihua; Das, Bhaskar; Zou, Yiyu; Young, Ken He; Parekh, Samir; Ye, B. Hilda.

In: Blood, Vol. 128, No. 24, 15.12.2016, p. 2797-2807.

Research output: Contribution to journalArticle

Mai, Y, Yu, JJ, Bartholdy, BA, Xu-Monette, ZY, Knapp, EE, Yuan, F, Chen, H, Ding, BB, Yao, Z, Das, B, Zou, Y, Young, KH, Parekh, S & Ye, BH 2016, 'An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL', Blood, vol. 128, no. 24, pp. 2797-2807. https://doi.org/10.1182/blood-2016-03-705814
Mai, Yun ; Yu, J. Jessica ; Bartholdy, Boris A. ; Xu-Monette, Zijun Y. ; Knapp, Esther E. ; Yuan, Fei ; Chen, Hongshan ; Ding, B. Belinda ; Yao, Zhihua ; Das, Bhaskar ; Zou, Yiyu ; Young, Ken He ; Parekh, Samir ; Ye, B. Hilda. / An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL. In: Blood. 2016 ; Vol. 128, No. 24. pp. 2797-2807.
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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 smallmolecule 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.",
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AU - Chen, Hongshan

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