Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

• Verfasst von: Nicolay, Jan Peter [VerfasserIn]
• Verfasst von: Géraud, Cyrill [VerfasserIn]
• Verfasst von: Goerdt, Sergij [VerfasserIn]
• Titel: Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB
• Verf.angabe: Jan P. Nicolay, Karin Müller-Decker, Anne Schroeder, Markus Brechmann, Markus Möbs, Cyrill Géraud, Chalid Assaf, Sergij Goerdt, Peter H. Krammer, and Karsten Gülow
• E-Jahr: 2016
• Jahr: June 7, 2016
• Umfang: 11 S.
• Fussnoten: Gesehen am 13.08.2019
• Titel Quelle: Enthalten in: Blood
• Ort Quelle: Washington, DC : American Society of Hematology, 1946
• Jahr Quelle: 2016
• Band/Heft Quelle: 128(2016), 6, Seite 805-815
• ISSN Quelle: 1528-0020
• DOI: doi:10.1182/blood-2016-01-694117
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1671264398

Abstract

Despite intensive efforts in recent years, a curative therapy for cutaneous T-cell lymphoma (CTCL) has not yet been developed. Therefore, the establishment of new therapeutic approaches with higher efficacy rates and milder side effects is strongly desired. A characteristic feature of the malignant T-cell population in CTCL is resistance toward cell death resulting from constitutive NF-κB activation. Therefore, NF-κB-dependent cell death resistance represents an interesting therapeutic target in CTCL because an NF-κB-directed therapy would leave bystander T cells widely unaffected. We investigated the effects of dimethyl fumarate (DMF) on CTCL cells in vitro and in vivo. DMF induced cell death in primary patient-derived CD4+ cells and CTCL cell lines, but hardly in T cells from healthy donors. DMF-induced cell death was linked specifically to NF-κB inhibition. To study the impact of DMF in vivo, we developed 2 CTCL xenograft mouse models with different cutaneous localizations of the T-cell infiltrate. DMF treatment delayed the growth of CTCL tumors and prevented formation of distant metastases. In addition, DMF induced increased cell death in primary CTCL tumors and in liver metastases. In summary, DMF treatment represents a remarkable therapeutic option in CTCL because it restores CTCL apoptosis in vitro and in preclinical models in vivo and prevents spreading of the disease to distant sites. DMF treatment is of particular promise in CTCL because DMF is already in successful clinical use in the treatment of psoriasis and multiple sclerosis allowing fast translation into clinical studies in CTCL.