Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers
| Autor: | Khondaker Miraz Rahman, Elisabeth Jane Walsby, Christopher Fegan, David B Corcoran, David Edwin Thurston, Chris Pepper, Thomas R. Lewis, Andrea Pepper, Peter Giles, Kevin E. Ashelford |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Chronic lymphocytic leukemia Pyrrolobenzodiazepine Context (language use) Apoptosis Mice SCID Article Bortezomib 03 medical and health sciences chemistry.chemical_compound Benzodiazepines Mice 0302 clinical medicine Piperidines In vivo Mice Inbred NOD hemic and lymphatic diseases medicine Tumor Microenvironment RM0260 Animals Pyrroles Multiple myeloma Adenine NF-kappa B Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology chemistry Cell culture 030220 oncology & carcinogenesis Ibrutinib Hematologic Neoplasms Cancer research medicine.drug |
| Zdroj: | Lewis, T, Corcoran, D B, Thurston, D E, J. Giles, P, Ashelford, K, Walsby, E J, Fegan, C D, Pepper, A G S, Rahman, K M & Pepper, C 2020, ' Novel pyrrolobenzodiazepine (PBD) benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers ', Haematologica, vol. Early view, 238584 . https://doi.org/10.3324/haematol.2019.238584 Haematologica |
| ISSN: | 0390-6078 |
| Popis: | Chronic lymphocytic leukemia (CLL) and multiple myeloma are incurable hematologic malignancies that are pathologically linked with aberrant nuclear factor-kappa B (NF-κB) activation. In this study, we identified a group of novel C8-linked benzofused pyrrolo[2,1- c][1,4]benzodiazepine monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and multiple myeloma cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4 h of exposure, demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNAsequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the downregulated gene list. Furthermore, in vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC- 1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P=0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease. |
| Databáze: | OpenAIRE |
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