Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

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-κB 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-κB 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-κB inhibitors in treating CTCL. Next, this potential should be explored further in a clinical study.

Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma

“…NT1721 also significantly decreased BCL2 expression in HuT78 (Figure 2A,B). However, in line with previous reports [17,34], no BCL2 mRNA or protein expression could be detected in HH cells.…”

“…Adding BCL2 or BCL2/BCL-xL inhibitors to the treatment of CTCL cells with other agents (e.g., histone deacetylase or bromodomain inhibitors) synergistically increased apoptosis induction [7,17,34,45,46]. In contrast, no synergy was observed when BCL2-negative HH cells were treated with the drug combinations [17,34]. Moreover, it has been shown that antiapoptotic BCL2 proteins have a role in promoting hedgehog/GLI signaling by enhancing the turnover of a GLI antagonist, SUFU tumor suppressor.…”

“…Relapses are common and treatment for the aggressive forms remains palliative, not curative despite recent advances with chemotherapeutic and biological approaches [4]. Moreover, current therapies often lead to progressive drug resistance [17]. Thus, new treatment options for advanced CTCL are urgently needed.…”

Update on Biology of Cutaneous T-Cell Lymphoma

“…The synergistic epigenetic-modulatory effect of histone acetylation of DNA demethylation results in global CpG methylation alterations as well as reexpression of tumor suppressor genes that was not achieved by single agent treatments (85). Preclinical and clinical investigations have demonstrated the combinatorial use of different epigenetic modulators together or in combination with other treatments (85)(86)(87)(88)(89)(90).…”

Molecular pathogenesis of cutaneous lymphoma–Future directions

“…The used drug is dimethyl fumarate and inhibitor of the NFκB activation. [24,25] Further interest was directed on T-cell receptor sequencing.…”