DCZ3301, a novel cytotoxic agent, inhibits proliferation in diffuse large B-cell lymphoma via the STAT3 pathway

Sun, Xi; Li, Bo; Xie, Bingqian; Xu, Zhijian; Chang, Gaomei; Yi, Tao; Zhang, Yong; Chang, Shuaikang; Wang, Yingcong; Yu, Dandan; Xie, Yongsheng; Li, Tingye; Wang, Houcai; Chen, Gege; Hu, Liangning; Hou, Jun; Zhang, Yiwen; Xiao, Wenqin; Shi, Jumei; Zhu, Weiliang

doi:10.1038/cddis.2017.472

Cited by 12 publications

(3 citation statements)

References 48 publications

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“…Specifically, gene set enrichment analysis (GSEA) analysis revealed that genes involved in the JAK-STAT signalling pathway were upregulated in ABC and downregulated in GCB. As both STAT3 and NF-kB have been identified as therapeutic targets for DLBCL, the network analysis here confirms the biological link between the genomic loci in the DLBCL-CCS and mechanisms of disease progression and supports the prognostic and monitoring capabilities of the EpiSwitch CCSs identified here [50][51][52][53]. In addition to validating known mechanisms of DLBCL, the network analysis here identified a novel potential target for therapeutic intervention in DLBCL.…”

Section: Discussionsupporting

confidence: 79%

Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies

Hunter¹,

McCord²,

Ramadass³

et al. 2020

transl med commun

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Background Diffuse large B-cell lymphoma (DLBCL) is a heterogenous blood cancer, but can be broadly classified into two main subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). GCB and ABC subtypes have very different clinical courses, with ABC having a much worse survival prognosis. It has been observed that patients with different subtypes also respond differently to therapeutic intervention, in fact, some have argued that ABC and GCB can be thought of as separate diseases altogether. Due to this variability in response to therapy, having an assay to determine DLBCL subtypes has important implications in guiding the clinical approach to the use of existing therapies, as well as in the development of new drugs. The current gold standard assay for subtyping DLBCL uses gene expression profiling on formalin fixed, paraffin embedded (FFPE) tissue to determine the “cell of origin” and thus disease subtype. However, this approach has some significant clinical limitations in that it 1) requires a biopsy 2) requires a complex, expensive and time-consuming analytical approach and 3) does not classify all DLBCL patients. Methods Here, we took an epigenomic approach and developed a blood-based chromosome conformation signature (CCS) for identifying DLBCL subtypes. An iterative approach using clinical samples from 118 DLBCL patients was taken to define a panel of six markers (DLBCL-CCS) to subtype the disease. The performance of the DLBCL-CCS was then compared to conventional gene expression profiling (GEX) from FFPE tissue. Results The DLBCL-CCS was accurate in classifying ABC and GCB in samples of known status, providing an identical call in 100% (60/60) samples in the discovery cohort used to develop the classifier. Also, in the assessment cohort the DLBCL-CCS was able to make a DLBCL subtype call in 100% (58/58) of samples with intermediate subtypes (Type III) as defined by GEX analysis. Most importantly, when these patients were followed longitudinally throughout the course of their disease, the EpiSwitch™ associated calls tracked better with the known patterns of survival rates for ABC and GCB subtypes. Conclusion This proof-of-concept study provides an initial indication that a simple, accurate, cost-effective and clinically adoptable blood-based diagnostic for identifying DLBCL subtypes is possible.

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Section: Discussionsupporting

confidence: 79%

Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies

Hunter¹,

McCord²,

Ramadass³

et al. 2020

transl med commun

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“…DCZ3301 is a novel aryl-guanidino compound synthesized by our group. We have previously reported that it exhibits strong anti-cancer activity in MM 13 , diffuse large B-cell lymphoma (DLBCL) [13] and T-cell leukemia/lymphoma [14]. Results from our studies have so far indicated that DCZ3301 possesses a strong ability to block cancer cells in the G 2 /M phase.…”

Section: Introductionmentioning

confidence: 76%

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe

Chen

et al. 2020

J Exp Clin Cancer Res

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Background: DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown. Methods: We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models. Results: DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G 2 /M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933. Conclusions: Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.

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“…17,18 The pathogenesis of DLBCL is complicated, being involved in different genetic and epigenetic changes. 19,20 Recently, miRNAs were reported to be associated with the formation and development of DLBCL. 6,7 miR-101 is reported to be associated with tumor formation and plays key roles in cell apoptosis, proliferation, migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

<p>miR-101 regulates cell proliferation and apoptosis by targeting KDM1A in diffuse large B cell lymphoma</p>

Huang¹,

Zou²,

Lin³

et al. 2019

CMAR

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Background miR-101 is reported to be associated with cell proliferation and apoptosis. However, it is unknown whether miR-101 expression affects cell proliferation and apoptosis in diffuse large B cell lymphoma (DLBCL). The aim of the present study was to investigate the expression of miR-101 and its effect on cell proliferation and apoptosis in DLBCL. Methods miR-101 expression was detected in 30 cases of patients with DLBCL and normal lymph node by qRT-PCR. Then, miR-101 expression was up-regulated and down-regulated in Originated Cell Line-Large Lymphoma 8 (OCL-LY8) cell line, respectively. MTT and flow cytometry assay were used to evaluate the effect of miR-101 on cell proliferation and apoptosis, respectively. As KDM1A was confirmed to be as a specific target of miR-101 by TargetScanHuman, the relationship between MiR-101 and KDM1A was further investigated. Results miR-101 expression in patients with DLBCL was significantly reduced compared those in normal lymph node (P<0.05). miR-101 expression was significantly associated with tumor size, clinical stage and International Prognostic Index (IPI) scores (P<0.05). In OCL-LY8 cell line, miR-101 down-regulation significantly promoted cell proliferation and suppressed cell apoptosis. Meanwhile, miR-101 up-regulation reversed this effect. In addition, miR-101 negatively regulated the expression of KDM1A. KDM1A down-regulation was oberved in normal tissues compared with those in DLBCL tissues, which inhibited cell proliferation and promoted cell apoptosis. Conclusion These data indicate that miR-101 regulates cell proliferation and apoptosis by targeting KDM1A, which provides a potential therapeutic for DLBCL patients.

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DCZ3301, a novel cytotoxic agent, inhibits proliferation in diffuse large B-cell lymphoma via the STAT3 pathway

Cited by 12 publications

References 48 publications

Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies

Comparative molecular cell-of-origin classification of diffuse large B-cell lymphoma based on liquid and tissue biopsies

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe

<p>miR-101 regulates cell proliferation and apoptosis by targeting KDM1A in diffuse large B cell lymphoma</p>

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