| AJTR Copyright © 2009-present, All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Am J Transl Res 2013;5(2):170-183
Original Article
The histone deacetylase inhibitor valproic acid sensitizes diffuse large
B-cell lymphoma cell lines to CHOP-induced cell death
Malin Ageberg, Karin Rydström, Thomas Relander, Kristina Drott
Division of Hematology and Transfusion Medicine, Lund University, BMC B13, Klinikg. 26, S-22184 Lund,
Sweden; Skåne Department of Oncology, Lund University Hospital, S-22185 Lund, Sweden
Received February 13, 2013; Accepted March 5, 2013; Epub March 28, 2013; Published April 8, 2013
Abstract: Epigenetic code modifications by histone deacetylase inhibitors (HDACis) have recently been proposed
as potential new therapies for hematological malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most
common form of aggressive lymphoma. At present, standard first line treatment for DLBCL patients is the
antracycline-based chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)
combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). Since only 50-60% of patients reach a
long-time cure by this treatment, there is an urgent need for novel treatment strategies to increase the response
and long-term remission to initial R-CHOP therapy. In this study, we investigated the effect of the HDAC inhibitor
valproic acid (VPA) on DLBCL cell lines. To elucidate the effects of VPA on chemo-sensitivity, we used a cell-line
based model of CHOP-refractory DLBCL. All five DLBCL cell lines treated with VPA alone or in combination with
CHOP showed decreased viability and proliferation. The VPA-induced sensitization of DLBCL cells to cytotoxic
treatment resulted in increased number of apoptotic cell as judged by annexin V-positivity and the presence of
cleaved caspase-3. In addition, pretreatment with VPA resulted in a significantly increased DNA-damage as
compared to CHOP alone. In summary, HDAC inhibitors such as VPA, are promising therapeutic agents in
combination with R-CHOP for patients with DLBCL (AJTR1302007).
Keywords: Non-Hodgkins lymphoma, valproic acid, valproate, HDAC
Address correspondence to: Dr. Kristina Drott, Department of Hematology and Transfusion Medicine, Lund
University, BMC B13, Klinikg. 26, S-221 84 Lund, Sweden. Phone: +46-46-2220632; Fax: +46-46-184493; E-mail:
Kristina.Drott@med.lu.se
Original Article
The histone deacetylase inhibitor valproic acid sensitizes diffuse large
B-cell lymphoma cell lines to CHOP-induced cell death
Malin Ageberg, Karin Rydström, Thomas Relander, Kristina Drott
Division of Hematology and Transfusion Medicine, Lund University, BMC B13, Klinikg. 26, S-22184 Lund,
Sweden; Skåne Department of Oncology, Lund University Hospital, S-22185 Lund, Sweden
Received February 13, 2013; Accepted March 5, 2013; Epub March 28, 2013; Published April 8, 2013
Abstract: Epigenetic code modifications by histone deacetylase inhibitors (HDACis) have recently been proposed
as potential new therapies for hematological malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most
common form of aggressive lymphoma. At present, standard first line treatment for DLBCL patients is the
antracycline-based chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)
combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). Since only 50-60% of patients reach a
long-time cure by this treatment, there is an urgent need for novel treatment strategies to increase the response
and long-term remission to initial R-CHOP therapy. In this study, we investigated the effect of the HDAC inhibitor
valproic acid (VPA) on DLBCL cell lines. To elucidate the effects of VPA on chemo-sensitivity, we used a cell-line
based model of CHOP-refractory DLBCL. All five DLBCL cell lines treated with VPA alone or in combination with
CHOP showed decreased viability and proliferation. The VPA-induced sensitization of DLBCL cells to cytotoxic
treatment resulted in increased number of apoptotic cell as judged by annexin V-positivity and the presence of
cleaved caspase-3. In addition, pretreatment with VPA resulted in a significantly increased DNA-damage as
compared to CHOP alone. In summary, HDAC inhibitors such as VPA, are promising therapeutic agents in
combination with R-CHOP for patients with DLBCL (AJTR1302007).
Keywords: Non-Hodgkins lymphoma, valproic acid, valproate, HDAC
Address correspondence to: Dr. Kristina Drott, Department of Hematology and Transfusion Medicine, Lund
University, BMC B13, Klinikg. 26, S-221 84 Lund, Sweden. Phone: +46-46-2220632; Fax: +46-46-184493; E-mail:
Kristina.Drott@med.lu.se
 | |  | |  | |  | |  | |  | |  |