Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

Bates, Darcy; Feris, Edmond J; Danilov, Alexey V.; Eastman, Alan

doi:10.1080/15384047.2016.1139245

Cited by 17 publications

(22 citation statements)

References 31 publications

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“…One study in CLL cells demonstrated vinca alkaloid‐mediated apoptosis in 48 h . However, we have recently shown that clinical concentrations of vinca alkaloids or BNC105 can induce CLL apoptosis in only 6 h . As these cells are almost exclusively in G0 this clearly reflects a nonmitotic activity.…”

Section: Consequences Of Microtubule Disruptionmentioning

confidence: 87%

“…It is known that JNK can induce Noxa gene transcription, but it is not required in all cell models, suggesting alternative pathways for Noxa upregulation by MDAs. This JNK‐Noxa‐apoptosis pathway is unique to MDAs as taxanes did not yield any of these acute signals in leukaemia .…”

Section: Consequences Of Microtubule Disruptionmentioning

confidence: 91%

“…A panel of 15 leukaemia and lymphoma cell lines including patient-derived CLL cells revealed JNK activation in response to vinblastine within 4 h, with the exception of Jurkat cells that have a known defect in their JNK pathway [45]. Several of the mantle cell lymphomas and patientderived CLL cells were innately sensitive to single agent vinblastine, with JNK activation at 30 min and apoptosis in 4-6 h. Follow up studies demonstrated acute (4-6 h) JNKdependent apoptosis by vinblastine, CA4 and BNC105 in leukaemia models [37,39]. Furthermore, JNK was required for apoptosis induced by vinblastine in combination with a CDK 7/9 inhibitor in leukaemia but not normal leucocytes [37].…”

Section: Kinase Activationmentioning

confidence: 99%

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Microtubule destabilising agents: far more than just antimitotic anticancer drugs

Bates

Eastman

2016

Brit J Clinical Pharma

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249

213

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Vinca alkaloids have been approved as anticancer drugs for more than 50 years. They have been classified as cytotoxic chemotherapy drugs that act during cellular mitosis, enabling them to target fast growing cancer cells. With the evolution of cancer drug development there has been a shift towards new "targeted" therapies to avoid the side effects and general toxicities of "cytotoxic chemotherapies" such as the vinca alkaloids. Due to their original classification, many have overlooked the fact that vinca alkaloids, taxanes and related drugs do have a specific molecular target: tubulin. They continue to be some of the most effective anticancer drugs, perhaps because their actions upon the microtubule network extend far beyond the ability to halt cells in mitosis, and include the induction of apoptosis at all phases of the cell cycle. In this review, we highlight the numerous cellular consequences of disrupting microtubule dynamics, expanding the textbook knowledge of microtubule destabilising agents and providing novel opportunities for their use in cancer therapy. Tables of Links

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Section: Consequences Of Microtubule Disruptionmentioning

confidence: 87%

Section: Consequences Of Microtubule Disruptionmentioning

confidence: 91%

Section: Kinase Activationmentioning

confidence: 99%

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Microtubule destabilising agents: far more than just antimitotic anticancer drugs

Bates

Eastman

2016

Brit J Clinical Pharma

Self Cite

249

213

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“…For example, Sal-like protein 2 and SP1 share similar DBEs and properties and may cooperatively bind together (56). Furthermore, apoptosis mediated by BNC105, a microtubule-disrupting compound, also led to JNK activation that promoted phosphorylation of ATF2 and induction of ATF3 and Noxa (31). Another study using proteasome inhibitor MG-132 for the induction of apoptosis in MEFs also discovered that JNK1 is needed to trigger cell death and required the presence of c-Myc, but the knockdown did not affect the expression of Noxa (32).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have also suggested ATF2, ATF3, and ATF4 as potential transcription factors of Noxa expression (31,32). To understand how Noxa is upregulated after UA treatment, we tested a variety of signaling pathways that may induce Noxa in RASFs, including hypoxia and JNK/ stress-activated protein kinase pathways, as well as pathways that regulate survival, such as Akt and activation of c-Jun.…”

Section: Ua-induced Noxa Upregulation Is Mediated Through Jnk Pathwaymentioning

confidence: 99%

Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1‐mediated Noxa expression and proteasomal degradation of Mcl‐1

et al. 2018

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Rheumatoid arthritis (RA) is characterized by hyperplastic pannus formation mediated by activated synovial fibroblasts (RASFs) that cause joint destruction. We have shown earlier that RASFs exhibit resistance to apoptosis, primarily as a result of enhanced expression of myeloid cell leukemia-1 (Mcl-1). In this study, we discovered that ursolic acid (UA), a plant-derived pentacyclic triterpenoid, selectively induces B-cell lymphoma 2 homology 3-only protein Noxa in human RASFs. We observed that UA-induced Noxa expression was followed by a consequent decrease in Mcl-1 expression in a dose-dependent manner. Subsequent evaluation of the signaling pathways showed that UA-induced Noxa is primarily mediated by the JNK pathway in human RASFs. Chromatin immunoprecipitation (IP) studies into the promoter region of Noxa indicated the role of transcription factor specificity protein 1 in JNK-mediated Noxa expression. Furthermore, the results from IP studies and proximity ligation assays indicated that UA-induced Noxa colocalizes and associates with Mcl-1 to prime it for proteasomal degradation through K-linked ubiquitination by the selective recruitment of Mcl-1 ubiquitin ligase E3, a homologous to E6-associated protein C terminus domain-containing E3 ubiquitin ligase. These findings unveil a novel mechanism of inducing apoptosis in RASFs and a potential adjunct therapeutic strategy of regulating synovial hyperplasia in RA.-Kim, E. Y., Sudini, K., Singh, A. K., Haque, M., Leaman, D., Khuder, S., Ahmed, S. Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

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A phase I trial of BNC105P and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

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Ness

Danilov

et al. 2022

eJHaem

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Chronic lymphocytic leukemia (CLL) was projected to cause 4320 deaths in 2021 in the US [1]. Chemo-immunotherapy regimens are commonly associated with unfavorable adverse events (AEs) [2, 3]. Targeted therapies such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib are better tolerated and have become standard of care for CLL. Ibrutinib causes egress of CLL cells from their stromal niche leading to peripheral lymphocytosis [4]. While initially successful in treatment of naïve, relapsed/refractory, and high risk CLL (deletion 17p), most high risk patients experienced disease progression, indicating a need to improve BTK-targeted therapy regimens [5-8]. Microtubule inhibitors kill CLL cells ex vivo with dependence on c-Jun N-terminal kinase (JNK) activation and induction of NOXA [9]. Vincristine activated JNK but not NOXA in circulating CLL cells in vivo [10]. BNC105, a colchicine-site microtubule inhibitor, was more potent at activating the JNK-NOXA apoptotic cascade [11]. BNC105P, the prodrug of BNC105, had a monotherapy maximum tolerated dose (MTD) of 16 mg/m 2 in solid tumor patients with on-target polymerized tubulin reduction activity starting at 12.6 mg/m 2 [12]. The study rationale was to target CLL cell egress from the stromal niche with ibrutinib and eliminate CLL cells in circulation with BNC105P to potentially obtain deep, long-lasting responses [13]. We therefore conducted an open-label, Phase Ib, dose escalation study of BNC105P and ibrutinib in patients with relapsed/refractory CLL (NCT03454165). Patients were enrolled at the Dartmouth Cancer Center using a Dartmouth College and Dartmouth-Hitchcock Health Institutional Review Board approved protocol and written informed consent. Study patients provided written informed consent prior to the performance of any study procedures and given a copy of the signed written informed consent.BNC105P (Bionomics Limited, Thebarton, Australia) was administered via IV infusion on days 1 and 8 (cycle 1) and days 8 and 15 (cycles 2-6) of 21-day cycles. Ibrutinib 420 mg was self-administered orally on days 1-21 (cycles 2-6). In drug combination cycles, ibrutinib was taken ≥30 min prior to BNC105P infusion. A standard 3 + 3 Phase I dose escalation design was used with planned BNC105P dose cohorts of 8 mg/m 2 (cohort 1), 12 mg/m 2 (cohort 2), and 16 mg/m 2 (cohort 3).The primary study objective was to determine the MTD of BNC105P in combination with ibrutinib in CLL patients.All patient inclusion and exclusion criteria for study NCT03454165 are detailed at https://clinicaltrials.gov/ct2/show/NCT03454165.

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Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

Cited by 17 publications

References 31 publications

Microtubule destabilising agents: far more than just antimitotic anticancer drugs

Microtubule destabilising agents: far more than just antimitotic anticancer drugs

Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1‐mediated Noxa expression and proteasomal degradation of Mcl‐1

A phase I trial of BNC105P and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

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