The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells<i>in vitro</i>, as a single agent and in combination with other drugs

Paulus, Aneel; Masood, Aisha; Miller, Kena C.; Khan, Aalia; Akhtar, Drusilla; Advani, Pooja; Foran, James M.; Rivera, Candido E.; Roy, Vivek; Colón‐Otero, Gerardo; Chitta, Kasyapa S.; Chanan‐Khan, Asher

doi:10.1111/bjh.12731

Cited by 5 publications

(5 citation statements)

References 41 publications

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“…Ixazomib has been reported to induce apoptosis in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) as a single agent or in combination with other chemotherapeutic agents 21 24 . Thus, we hypothesized that ixazomib may induce apoptosis in NB cells.…”

Section: Resultsmentioning

confidence: 99%

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Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

Chen

et al. 2016

Sci Rep

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Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients.

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Section: Resultsmentioning

confidence: 99%

“…Dox induces apoptosis in tumor cells by causing DNA damage 25 , and ixazomib has been shown to induce apoptosis in CLL cells in combination with other agents 24 . Therefore, we hypothesized that inhibition of proteasome activity by ixazomib may increase the chemosensitivity of NB cells to dox.…”

Section: Resultsmentioning

confidence: 99%

Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

Chen

et al. 2016

Sci Rep

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“…10–13 All cells were cultured in AIM-V media under conditions previously reported by us. 10,11 CD38 receptor density on CLL cells was quantified as MFI and cell surface antibody bound/cell (sAbc). For certain experiments, PBMCs were isolated from Patients 4, 18, 19, 28 and 31 and CD19/CD5+ CLL cells were selected out using magnetic beads, followed by flow sorting with an anti-CD38 APC antibody for separation of CD19+/CD38 hi and CD19+/CD38 lo purified cells.…”

Section: Methodsmentioning

confidence: 99%

Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia

Manna

Aulakh

Jani

et al. 2019

Clinical Cancer Research

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Purpose: CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 monoclonal antibody). The clinical importance of CD38 in chronic lymphocytic leukemia (CLL) patients has been known for over two decades, though it’s relevance as a therapeutic target in CLL remains understudied. Experimental Design: We investigated the biological effects and anti-tumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (ADCC, CDC and ADCP), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo anti-leukemic activity was assessed in a partially-humanized xenograft model. The influence of CD38 on BCR signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2 and AKT. Results: In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR crosslinking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2 and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model. Conclusions: Overall, our data demonstrate the anti-tumor mechanisms of daratumumab in CLL; furthermore, we show how co-targeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.

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“… [ 29 ] Ixazomib Primary CLL cells Annexin-V staining, PARP1 and caspase-3 cleavage and an increase in mitochondrial membrane permeability, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD-fmk. [ 66 ] Updated from Franke et al [ 67 ] Abbreviations: PSI N-carbobenzoxy-L-isoleucyl-L-γ-t-butyl-L-glutamyl-L-alanyl-L-leucinal, LLnV N-Carbobenzoxy-L-leucyl-L-norvalinal, LLnL N-acetylleucylleucylnorleucinal, MG-132 Carbobenzoxy-L-leucyl-L-leucyl-leucinal, GC glucocorticoid, PKC protein kinase C …”

Section: Proteasome Inhibitors In Leukemiamentioning

confidence: 99%

(Immuno)proteasomes as therapeutic target in acute leukemia

Cloos

Roeten

Franke

et al. 2017

Cancer Metastasis Rev

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The clinical efficacy of proteasome inhibitors in the treatment of multiple myeloma has encouraged application of proteasome inhibitor containing therapeutic interventions in (pediatric) acute leukemia. Here, we summarize the positioning of bortezomib, as first-generation proteasome inhibitor, and second-generation proteasome inhibitors in leukemia treatment from a preclinical and clinical perspective. Potential markers for proteasome inhibitor sensitivity and/or resistance emerging from leukemia cell line models and clinical sample studies will be discussed focusing on the role of immunoproteasome and constitutive proteasome (subunit) expression, PSMB5 mutations, and alternative mechanisms of overcoming proteolytic stress.

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The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cellsin vitro, as a single agent and in combination with other drugs

Cited by 5 publications

References 41 publications

Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia

(Immuno)proteasomes as therapeutic target in acute leukemia

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