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Novel PBD inhibit NF-κB in hematologic cancers
addition of bortezomib and ibrutinib, respectively. Furthermore, the combination of DC-1-192 with borte- zomib and ibrutinib showed synergy (CI values <1) at the level of LD50, LD75 and LD90 with an incremental increase in synergistic effect from LD50 to LD90 (Figure 6C). Furthermore, DC-1-192 showed increased synergy with ibrutinib when primary CLL cells were co-cultured on CD40L-expressing fibroblasts (Figure 6D) suggesting that these agents may be particularly effective in the treat- ment of tissue-resident CLL cells.
Discussion
NF-κB is a master regulator of a number of cellular processes that contribute to cancer progression, including cell survival and proliferation. Furthermore, it is often implicated in drug resistance, highlighting its potential as a therapeutic target.12,13 The interest in small molecular DNA-binding agents, such as the PBD monomers, has increased in recent years due to their ability to selectively bind to specific sequences within the minor groove of DNA, a characteristic that separates them from traditional
AB
CD
Figure 6. DC-1-192 demonstrates cytotoxic synergy with bortezomib and ibrutinib. Synergy between DC-1-192 and bortezomib was experimentally determined in JJN3 cells and between DC-1-192 and ibrutinib in primary chronic lymphocytic leukemia (CLL) cells. The fixed molar ratios for each combination were derived from
values for DC-1-192 and the clinically achievable doses of bortezomib and ibrutinib. Apoptosis was determined using the annexin V/propidium iodide assay. (A) The fraction affected plot and the isobologram plot for DC-1-192, bortezomib and their respective combination (1:15) in JJN3 cells. (B) The fraction affected plot and isobologram plot for DC-1-192, ibrutinib and their combination (1:3000) in primary cells. (C) The combination indices for the combination DC-1-192 with
50
the mean LD
50
, LD 75
and LD 90
in primary CLL cells (n=5). (D) Comparison of the combination indices generated by the com- bination of DC-1-192 and ibrutinib in monoculture and CD40L-expressing co-culture. All JJN3 cell line experiments were performed in triplicate. All of the primary
bortezomib and DC-1-192 with ibrutinib at the level of LD
CLL experiments were performed on samples derived from five individual patients with data presented as the mean of duplicate experiments.
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