The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia

Manzoni, Delphine; Catallo, Régine; Chebel, Amel; Baseggio, Lucile; Michallet, Anne‐Sophie; Roualdes, O.; Magaud, Jean‐Pierre; Salles, Gilles; Ffrench, Martine

doi:10.1016/j.leukres.2016.05.003

Cited by 10 publications

(6 citation statements)

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“…37 A combination of ibrutinib with other drugs such as dexamethasone targeting alternative pathways that are independent of BTK signaling could be additive or synergistic. 38 In a recent in-vitro study, Manzoni et al showed that dexamethasone potentiated anti-proliferative effects of ibrutinib. 38 Consistent with the previous studies, we demonstrated a significant decrease of cell proliferation with the combination of ibrutinib and dexamethasone in both Raji and Ramos with a significant reduction of IC 50 compared to ibrutinib alone ( Figure 2C-D).…”

Section: Discussionmentioning

confidence: 99%

“…38 In a recent in-vitro study, Manzoni et al showed that dexamethasone potentiated anti-proliferative effects of ibrutinib. 38 Consistent with the previous studies, we demonstrated a significant decrease of cell proliferation with the combination of ibrutinib and dexamethasone in both Raji and Ramos with a significant reduction of IC 50 compared to ibrutinib alone ( Figure 2C-D). Our data indicates that the use of a dexamethasone and ibrutinib combination may be an active combination in patients with BL.…”

Section: Discussionmentioning

confidence: 99%

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Ibrutinib significantly inhibited Bruton’s tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model

et al. 2018

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Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p < 0.001). Moreover, we observed a significant decrease in cell proliferation as well as significant decrease in IC 50 of ibrutinib in combination with dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001). In-vivo studies demonstrated ibrutinib treated mice had a significantly prolonged survival with median survival of mice following ibrutinib treatment (32 days) (24 days) (p < 0.02). In conclusion, our findings demonstrate the significant in-vitro and preclinical in-vivo effects of ibrutinib in BL. Based on our preclinical results in this investigation, there is an ongoing clinical trial comparing overall survival in children and adolescents with relapsed/ refractory BL treated with chemoimmunotherapy with or without ibrutinib (NCT02703272).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ibrutinib significantly inhibited Bruton’s tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model

et al. 2018

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“…In 2016, Manzoni et al analyzed the in vitro effects of the combination of ibrutinib and dexamethasone on the proliferation and metabolic stress markers in lymphocytes obtained from patients suffering from CLL. They demonstrated an enhanced inhibition of cell cycle progression, an increase in apoptosis and a decrease in DNA damage in lymphoid B cells by a combination of dexamethasone and ibrutinib compared to the tyrosine kinase inhibitor alone (259).…”

Section: Mechanisms Of Glucocorticoids In the Treatment Of Malignancimentioning

confidence: 99%

Glucocorticoids—All-Rounders Tackling the Versatile Players of the Immune System

et al. 2019

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Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia.

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“…More particularly, the covalent-binding BTK inhibitor IBR has shown to be a potent anticancer drug in chronic lymphocytic leukemia (CLL), mantle cell lymphoma, diffuse large B-cell lymphoma, and MM by interfering with B-cell homing, survival and microenvironment-mediated drug resistance [17,18,[22][23][24][25]. Suppression of BTK hyperactivation is also key to the therapeutic efficacy of GCs in B-cell leukemias, where IBR has been shown to improve GC therapy response [26][27][28][29]. In clinical trials of MM, combination therapies investigating IBR efficiency demonstrated encouraging responses and a manageable safety profile [30,31].…”

Section: Introductionmentioning

confidence: 99%

Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

Logie

Chirumamilla

Pérez-Novo

et al. 2021

Cancers

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Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells’ uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA’s promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM.

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The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia

Cited by 10 publications

References 29 publications

Ibrutinib significantly inhibited Bruton’s tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model

Ibrutinib significantly inhibited Bruton’s tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model

Glucocorticoids—All-Rounders Tackling the Versatile Players of the Immune System

Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

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