Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate

Autoren

Efferth

DOI

10.3892/ijo_00000323

ISSN

1019-6439

Ausgabe der Veröffentlichung

01

Zeitschrift

International Journal of Oncology

Datum der Veröffentlichung

2009

Status

Published

Herausgeber

Spandidos Publications

Herausgeber URL

http://dx.doi.org/10.3892/ijo_00000323

Datum der Datenerfassung

2017

Titel

Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate

Ausgabe der Zeitschrift

35

Data source: Crossref

Abstract

Chemotherapy of non-Hodgkin's lymphoma is frequently hampered by drug resistance. The monoclonal antibody rituximab specifically targets the CD20 antigen and sensitizes B-cell lymphoma cells to standard anticancer drugs. In the present investigation, we analyzed, whether a combination of rituximab and artesunate may act in a complementary manner and eventually synergize in tumor cell killing. Artesunate is an anti-malarial drug, which also exerts profound activity towards cancer cells. While rituximab alone was minimally cytotoxic, rituximab increased cytotoxicity to artesunate in Ramos cells. Artesunate induced apoptosis, induced Fas/CD95 expression and the formation of reactive oxygen species (ROS) and resulted in a breakdown of mitochondrial membrane potential. This argues for the involvement of both receptor-driven extrinsic and mitochondrial intrinsic routes of apoptosis. Rituximab increased Fas/CD95 expression and ROS formation and decreased mitochondrial membrane potential ultimately leading to increased apoptosis induced by artesunate. The transcription factors YY1 and Sp1 are upstream regulators of apoptosis by controlling the expression of apoptosis-regulating genes. YY1 and Sp1 were down-regulated and Fas/CD95 was up-regulated by rituximab and artesunate indicating that artesunate activated the Fas/CD95 pathway and that rituximab increased the susceptibility of tumor cells to artesunate-induced apoptosis. Furthermore, rituximab affected the expression of antioxidant genes. The antibody decreased artesunate-induced up-regulation of catalase expression and increased artesunate-induced down-regulation of glutathione S-transferase-phi expression. Manganese-dependent superoxide dismutase expression was not changed by artesunate. Antioxidant proteins may help to detoxify artesunate-induced ROS. Rituximab reversed the artesunate-induced expression changes of antioxidant genes and, hence, reduced the detoxification capacity of Ramos cells. The effects of rituximab on antioxidant genes represent a novel mechanism of rituximab for chemosensitization.

Addresses

German Cancer Research Center, Pharmaceutical Biology (C015), D-69120 Heidelberg, Germany.

Autoren

Sebastian Sieber
Georg Gdynia
Wilfried Roth
Benjamin Bonavida
Thomas Efferth
Thomas Efferth

DOI

10.3892/ijo_00000323

eISSN

1791-2423

Externe Identifier

PubMed Identifier: 19513562

Open access

false

ISSN

1019-6439

Ausgabe der Veröffentlichung

1

Zeitschrift

International journal of oncology

Schlüsselwörter

Cell Line, Tumor
Mitochondria
Humans
Lymphoma, B-Cell
Reactive Oxygen Species
Artemisinins
Catalase
Superoxide Dismutase
Antineoplastic Combined Chemotherapy Protocols
Antigens, CD20
Antibodies, Monoclonal
Antimalarials
Apoptosis
Cell Survival
Oxidative Stress
Dose-Response Relationship, Drug
Sp1 Transcription Factor
YY1 Transcription Factor
BH3 Interacting Domain Death Agonist Protein
Glutathione S-Transferase pi
Membrane Potential, Mitochondrial
Antibodies, Monoclonal, Murine-Derived
Rituximab
fas Receptor
Artesunate

Sprache

eng

Medium

Print

Paginierung

149 - 158

Datum der Veröffentlichung

2009

Status

Published

Datum der Datenerfassung

2009

Titel

Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate.

Sub types

Journal Article

Ausgabe der Zeitschrift

35

Data source: Europe PubMed Central

Abstract

Chemotherapy of non-Hodgkin's lymphoma is frequently hampered by drug resistance. The monoclonal antibody rituximab specifically targets the CD20 antigen and sensitizes B-cell lymphoma cells to standard anticancer drugs. In the present investigation, we analyzed, whether a combination of rituximab and artesunate may act in a complementary manner and eventually synergize in tumor cell killing. Artesunate is an anti-malarial drug, which also exerts profound activity towards cancer cells. While rituximab alone was minimally cytotoxic, rituximab increased cytotoxicity to artesunate in Ramos cells. Artesunate induced apoptosis, induced Fas/CD95 expression and the formation of reactive oxygen species (ROS) and resulted in a breakdown of mitochondrial membrane potential. This argues for the involvement of both receptor-driven extrinsic and mitochondrial intrinsic routes of apoptosis. Rituximab increased Fas/CD95 expression and ROS formation and decreased mitochondrial membrane potential ultimately leading to increased apoptosis induced by artesunate. The transcription factors YY1 and Sp1 are upstream regulators of apoptosis by controlling the expression of apoptosis-regulating genes. YY1 and Sp1 were down-regulated and Fas/CD95 was up-regulated by rituximab and artesunate indicating that artesunate activated the Fas/CD95 pathway and that rituximab increased the susceptibility of tumor cells to artesunate-induced apoptosis. Furthermore, rituximab affected the expression of antioxidant genes. The antibody decreased artesunate-induced up-regulation of catalase expression and increased artesunate-induced down-regulation of glutathione S-transferase-phi expression. Manganese-dependent superoxide dismutase expression was not changed by artesunate. Antioxidant proteins may help to detoxify artesunate-induced ROS. Rituximab reversed the artesunate-induced expression changes of antioxidant genes and, hence, reduced the detoxification capacity of Ramos cells. The effects of rituximab on antioxidant genes represent a novel mechanism of rituximab for chemosensitization.

Autoren

Sebastian Sieber
Georg Gdynia
Wilfried Roth
Benjamin Bonavida
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/19513562

DOI

10.3892/ijo_00000323

ISSN

1019-6439

Ausgabe der Veröffentlichung

1

Zeitschrift

Int J Oncol

Schlüsselwörter

Antibodies, Monoclonal
Antibodies, Monoclonal, Murine-Derived
Antigens, CD20
Antimalarials
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Artemisinins
Artesunate
BH3 Interacting Domain Death Agonist Protein
Catalase
Cell Line, Tumor
Cell Survival
Dose-Response Relationship, Drug
Glutathione S-Transferase pi
Humans
Lymphoma, B-Cell
Membrane Potential, Mitochondrial
Mitochondria
Oxidative Stress
Reactive Oxygen Species
Rituximab
Sp1 Transcription Factor
Superoxide Dismutase
YY1 Transcription Factor
fas Receptor

Sprache

eng

Country

Greece

Paginierung

149 - 158

Datum der Veröffentlichung

2009

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2009

Titel

Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate.

Sub types

Journal Article

Ausgabe der Zeitschrift

35

Data source: PubMed

Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate

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