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

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, characterized by a rapidly increasing painless mass. A novel compound, DCZ3301, was synthesized that exerted direct cytotoxicity against DLBCL cell lines. The effects of DCZ3301 on DLBCL cells in vitro and in vivo and the associated mechanisms were investigated. DCZ3301 inhibited the viability of DLBCL cell lines, even in the presence of protumorigenesis cytokines. Additionally, the compound induced apoptosis and cell cycle arrest at the G2/M phase by reducing mitochondrial membrane potential. DCZ3301 exerted an antitumor effect through modulation of Akt, extracellular signal-regulated kinases 1/2 (ERK1/2) and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. Furthermore, DCZ3301 downregulates STAT3 phosphorylation by inhibiting Lck/Yes-related novel protein tyrosine kinase (Lyn) activation in DLBCL. A synergistic cytotoxic effect on DLBCL cells was observed upon combination of DCZ3301 with panobinostat. In vivo, intraperitoneal injection of xenograft mice with DCZ3301 resulted in reduced tumor volume. Our preliminary results collectively support the utility of the small-molecule inhibitor DCZ3301 as an effective novel therapeutic option for DLBCL that requires further clinical evaluation.

SUBMITTER: Sun X

PROVIDER: S-EPMC5680593 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Sun Xi X Li Bo B Xie Bingqian B Xu Zhijian Z Chang Gaomei G Tao Yi Y Zhang Yong Y Chang Shuaikang S Wang Yingcong Y Yu Dandan D Xie Yongsheng Y Li Tingye T Wang Houcai H Chen Gege G Hu Liangning L Hou Jun J Zhang Yiwen Y Xiao Wenqin W Gao Lu L Shi Jumei J Zhu Weiliang W

Cell death & disease 20171012 10

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, characterized by a rapidly increasing painless mass. A novel compound, DCZ3301, was synthesized that exerted direct cytotoxicity against DLBCL cell lines. The effects of DCZ3301 on DLBCL cells in vitro and in vivo and the associated mechanisms were investigated. DCZ3301 inhibited the viability of DLBCL cell lines, even in the presence of protumorigenesis cytokines. Additionally, the compound induced apoptosis an ...[more]

PMID: 29022919

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Project description:Long-chain non-coding RNAs (LncRNAs) are expressed in diffuse large B-cell lymphoma (DLBCL) tissues and have played a regulatory role in DLBCL with a cancer-promoting effect. In this study, the role of LncRNA SNHG8 in the regulation of DLBCL cells is investigated, and its underlying mechanism is explored. The database of the Gene Expression Profiling Interactive Analysis (GEPIA) was searched, and the expression of SNHG8 in DLBCL and normal tissues was examined. The expression of SNHG8 was evaluated in several DLBCL cell lines and a normal lymphocyte cell line. It was found that SNHG8 was overexpressed in DLBCL tissues and cells in comparison with their normal counterparts. The short hairpin RNA (shRNA) plasmids of SNHG8 were transfected into DLBCL cells to knockdown the expression of SNHG8, followed by assays of proliferation, colony formation, apoptosis, and related protein expression. The results showed that the knockdown of SNHG8 significantly inhibited DLBCL cell proliferation and colony formation while promoting cell apoptosis. Moreover, the knockdown of SNHG8 reduced the expression of Ki-67, proliferating cell nuclear antigen (PCNA), and Bcl-2 and enhanced the expression of Bax and cleaved caspase 3/9. MiR-335-5p was predicted to be a potential target of SNHG8 by using the bioinformatics analysis, and the interaction between the two was validated by using the dual luciferase assay. In addition, the knockdown of SNHG8 increased the level of miR-335-5p, whereas miR-335-5p mimic decreased the expression of SNHG8. Finally, U2932 cells were co-transfected with or without sh-SNHG8 and miR-335-5p inhibitors, whose proliferation, colony formation, and apoptosis were determined subsequently. It was demonstrated that the presence of an miR-335-5p inhibitor partially canceled the inhibitory effects of the knockdown of SNHG8 on DLBCL cell proliferation and colony formation and the stimulating effects of the knockdown of SNHG8 on cell apoptosis. Taken together, our study suggests that lncRNA SNHG8 exerts a cancer-promoting effect on DLBCL via targeting miR-335-5p.

Dataset Information

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

Publications

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

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