Froehlich, Tabea C. and Mueller-Decker, Karin and Braun, Jana D. and Albrecht, Thomas and Schroeder, Anne and Guelow, Karsten and Goerdt, Sergij and Krammer, Peter H. and Nicolay, Jan P. (2019) Combined inhibition of Bcl-2 and NF kappa B synergistically induces cell death in cutaneous T-cell lymphoma. BLOOD, 134 (5). pp. 445-455. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)Abstract
Therapeutic options for cutaneous T-cell lymphoma (CTCL) are limited and curative treatment regimens are not available. Thus, new targeted and well-tolerated therapeutic approaches are urgently needed. In this respect, we have recently shown that dimethyl fumerate (DMF) inhibits NF-kappa B acting as a survival factor in CTCL. Similarly, inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) has been shown to induce cell death in CTCL especially when combined with histone deacetylase inhibitors. Therefore, we hypothesized that inhibition of Bcl-2 should potentiate NF-kappa B inhibition in a novel combination treatment of CTCL. We show that, in vitro, the Bcl-2 inhibitors ABT-199 and ABT-263 induced specific cell death in primary CD4(+) cells from CTCL patients as well as in the CTCL cell line SeAx, but not in T cells of healthy donors nor in the CTCL cell line HH, which lacks Bcl-2. Combined treatment with ABT-199 and DMF caused synergistic cell death specifically in CTCL cells engaging 2 independent signaling pathways. To verify these findings in vivo, we performed combined ABT-199 and DMF treatment in a xenograft mouse model for CTCL. The combined treatment effectively reduced tumor growth and increased overall survival via synergistic induction of CTCL cell death and suppression of tumor cell proliferation. Essentially, the combination treatment was superior to ABT-199 monotherapy with respect to both efficacy and tolerability. To sum up, our data provide proof of principle for the therapeutic potential of combining Bcl-2 and NF-kappa B inhibitors in treating CTCL. Next, this potential should be explored further in a clinical study.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MYCOSIS-FUNGOIDES; TUMOR-GROWTH; ACTIVATION; VENETOCLAX; EXPRESSION; RESISTANCE; SURVIVAL; PATHWAY; PROTEIN; PATHOGENESIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 05:00 |
| Last Modified: | 02 Apr 2020 05:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26532 |
Actions (login required)
 |
View Item |
