Page 106 - Haematologica3

Correspondence:
jing.wang@ucdenver.edu
Received: July 6, 2017.
Accepted: November 30, 2017. Pre-published: December 7, 2017.
doi:10.3324/haematol.2017.175992
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/466
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
Haematologica 2018 Volume 103(3):466-476
1Department of Immunology and Microbiology; 2Department of Medicine Division of Pulmonary Sciences and Critical Care Medicine and 3Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
Ferrata Storti Foundation
Non-Hodgkin Lymphoma
Chemotherapy-induced differential cell cycle arrest in B-cell lymphomas affects their sensitivity to Wee1 inhibition
Xiaoguang Wang,1 Zhangguo Chen,1 Ameet K. Mishra,1 Alexa Silva,1 Wenhua Ren,2 Zenggang Pan3 and Jing H. Wang1
ABSTRACT
Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B- cell lymphomas, and whether this phenotype can be exploited for devel- oping new therapies. We treated various types of B cells, including pri- mary and B lymphoma cells, with cytarabine or doxorubicin, and deter- mined DNA damage responses, cell cycle regulation and sensitivity to a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle. The Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B-cell lymphomas by inducing premature entry into mitosis and mitotic catas- trophe, whereas it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxoru- bicin treatment in certain B-cell lymphomas, which correlates with newly acquired sensitivity to the Wee1 inhibitor. Consequently, the Wee1 inhibitor together with cytarabine or doxorubicin inhibited tumor growth in vitro and in vivo more effectively, providing a potential new ther- apy for treating B-cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance the chemosensitivity of B-cell lymphomas.
Introduction
Cytarabine, known as Ara-C, rapidly converts to cytosine arabinoside triphos- phate, which can be incorporated into DNA during the process of DNA synthesis, and eventually causes DNA damage, probably by stalling replication forks and gen- erating DNA double-stranded breaks. Given that cancer cells proliferate rapidly, Ara-C can kill cancer cells by interfering with their DNA synthesis during the S phase of the cell cycle. Ara-C has been the backbone of induction chemotherapy for acute myeloid leukemia and acute lymphocytic leukemia for several decades.1,2 For non-Hodgkin lymphomas, Ara-C is used as an upfront therapy for mantle cell lym- phoma and Burkitt lymphoma, and as part of some salvage regimens when non- Hodgkin lymphomas relapse. However, it remains incompletely understood how Ara-C treatment regulates DNA damage responses in primary B cells and B-cell lym- phomas.
The current treatment of B-cell non-Hodgkin lymphomas typically includes R- CHOP, a combination of anti-CD20 (rituximab), three chemotherapy agents (cyclophosphamide, doxorubicin, vincristine), and one steroid (prednisone).3,4 This regimen has increased the rates of complete response for both young and elderly patients with diffuse large B-cell lymphoma.5,6 Both cyclophosphamide and doxoru- bicin are also DNA-damaging agents, although their functional mechanisms are dif- ferent from those of Ara-C. Doxorubicin is commonly used to treat cancers, includ- ing breast cancer, bladder cancer, lymphoma and acute lymphoblastic leukemia.7
466
haematologica | 2018; 103(3)
ARTICLE