Targeting metabolism and survival in chronic lymphocytic leukemia and richter syndrome cells by a novel NF-κB inhibitor Journal Article
| Authors: | Vaisitti, T.; Gaudino, F.; Ouk, S.; Moscvin, M.; Vitale, N.; Serra, S.; Arruga, F.; Zakrzewski, J. L.; Liou, H. C.; Allan, J. N.; Furman, R. R.; Deaglio, S. |
| Article Title: | Targeting metabolism and survival in chronic lymphocytic leukemia and richter syndrome cells by a novel NF-κB inhibitor |
| Abstract: | IT-901 is a novel and selective NF-κB inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells (CLL) with IT-901 effectively interrupts NF-κB transcriptional activity. CLL cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production, and activate intrinsic apoptosis. Inhibition of NF-κB signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-κB-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro-leukemic niche. The consequence is that accessory cells do not protect CLL cells from IT- 901-induced apoptosis. In this context, IT-901 shows synergistic activity with ibrutinib, arguing in favor of combination strategies. IT-901 is also effective in primary cells from patients with Richter syndrome (RS). Its anti-tumor properties are confirmed in xenograft models of CLL and in RS patient-derived xenografts, with documented NF-κB inhibition and significant reduction of tumor burden. Together, these results provide pre-clinical proof of principle for IT-901 as a potential new drug in CLL and RS. © 2017 Ferrata Storti Foundation. |
| Keywords: | immunohistochemistry; controlled study; human tissue; unclassified drug; human cell; nonhuman; flow cytometry; antineoplastic agent; mouse; metabolism; animal tissue; cell viability; cell survival; apoptosis; gene expression; confocal microscopy; cell infiltration; vascular cell adhesion molecule 1; animal experiment; animal model; mitochondrial membrane potential; immunoglobulin enhancer binding protein; enzyme linked immunosorbent assay; xenograft; lymphoma; reactive oxygen metabolite; genetic stability; immunomodulation; upregulation; gene silencing; adenosine triphosphate; tumor growth; dna binding; chronic lymphatic leukemia; cell interaction; oxygen consumption; oxidative phosphorylation; intercellular adhesion molecule 1; cd86 antigen; programmed death 1 ligand 1; tumor microenvironment; mitochondrial respiration; cytochrome c oxidase; transcription factor rel; catalase; richter syndrome; rotenone; ibrutinib; human; article; depolarization; whole exome sequencing; antimycin a1; it 901 |
| Journal Title: | Haematologica |
| Volume: | 102 |
| Issue: | 11 |
| ISSN: | 0390-6078 |
| Publisher: | Ferrata Storti Foundation |
| Date Published: | 2017-10-27 |
| Start Page: | 1878 |
| End Page: | 1889 |
| Language: | English |
| DOI: | 10.3324/haematol.2017.173419 |
| PROVIDER: | scopus |
| PMCID: | PMC5664392 |
| PUBMED: | 28860341 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 December 2017 -- Source: Scopus |
