Antitumor effect of BC12-3 on multiple myeloma via proteasome inhibition.

IF 2.8 4区 医学 Q2 ONCOLOGY
Huiying Li, Geng Jia, Naixin Zhang, Rui Fan, Wenqing Jia, Meihua Jin, Shingo Dan, Wennan Zhao, Yuqi Jiang, Dexin Kong
{"title":"Antitumor effect of BC12-3 on multiple myeloma via proteasome inhibition.","authors":"Huiying Li, Geng Jia, Naixin Zhang, Rui Fan, Wenqing Jia, Meihua Jin, Shingo Dan, Wennan Zhao, Yuqi Jiang, Dexin Kong","doi":"10.1007/s12032-025-02804-3","DOIUrl":null,"url":null,"abstract":"<p><p>Multiple myeloma (MM) ranks second only to lymphoma among hematologic malignancies in terms of incidence. Current treatment methods primarily rely on proteasome inhibitors (PIs) targeting the ubiquitin proteasome system (UPS). However, existing PIs regimens encounter several limitations, including severe adverse effects, rapidly developing resistance during treatment, and restricted therapeutic efficacy. In light of this, our work aims to explore strategies to mitigate poor conditions. We employed a systematic structural optimization process to design and synthesize the new compound BC12-3, based on prevailing PIs. JFCR39 COMPARE analysis was used to assess cytotoxic activity against 39 characteristic cancer cell lines, and the IC<sub>50</sub> value of BC12-3 was measured using CCK-8 assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry, while western blotting investigated the antitumor mechanism of BC12-3. In vivo efficacy and safety of BC12-3 and bortezomib (BTZ) were evaluated in the xenograft model. ADMET computational analyses estimated the biological safety of these two inhibitors. As a result, BC12-3 exhibited potent broad-spectrum antitumor activity in vitro particularly against MM cells; This effect was achieved by selectively inhibiting β5 subunit of proteasome activity. BC12-3 suppressed MM cell growth primarily via cell cycle arrest in G2/M phase and apoptosis induction, the related molecular pathways confirmed these phenomena. In vivo studies indicated that BC12-3 exhibits significant effect in inhibiting tumor growth, with its efficacy comparable to that of the standard therapeutic drug, BTZ. Additionally, this new compound showed an excellent safety profile. Consequently, BC12-3 holds promise as a novel therapeutic strategy for the treatment of MM.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"42 7","pages":"235"},"PeriodicalIF":2.8000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Medical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12032-025-02804-3","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Multiple myeloma (MM) ranks second only to lymphoma among hematologic malignancies in terms of incidence. Current treatment methods primarily rely on proteasome inhibitors (PIs) targeting the ubiquitin proteasome system (UPS). However, existing PIs regimens encounter several limitations, including severe adverse effects, rapidly developing resistance during treatment, and restricted therapeutic efficacy. In light of this, our work aims to explore strategies to mitigate poor conditions. We employed a systematic structural optimization process to design and synthesize the new compound BC12-3, based on prevailing PIs. JFCR39 COMPARE analysis was used to assess cytotoxic activity against 39 characteristic cancer cell lines, and the IC50 value of BC12-3 was measured using CCK-8 assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry, while western blotting investigated the antitumor mechanism of BC12-3. In vivo efficacy and safety of BC12-3 and bortezomib (BTZ) were evaluated in the xenograft model. ADMET computational analyses estimated the biological safety of these two inhibitors. As a result, BC12-3 exhibited potent broad-spectrum antitumor activity in vitro particularly against MM cells; This effect was achieved by selectively inhibiting β5 subunit of proteasome activity. BC12-3 suppressed MM cell growth primarily via cell cycle arrest in G2/M phase and apoptosis induction, the related molecular pathways confirmed these phenomena. In vivo studies indicated that BC12-3 exhibits significant effect in inhibiting tumor growth, with its efficacy comparable to that of the standard therapeutic drug, BTZ. Additionally, this new compound showed an excellent safety profile. Consequently, BC12-3 holds promise as a novel therapeutic strategy for the treatment of MM.

BC12-3通过蛋白酶体抑制对多发性骨髓瘤的抗肿瘤作用。
多发性骨髓瘤(MM)在血液学恶性肿瘤中发病率仅次于淋巴瘤。目前的治疗方法主要依赖于针对泛素蛋白酶体系统(UPS)的蛋白酶体抑制剂(pi)。然而,现有的pi方案存在一些局限性,包括严重的不良反应,治疗期间迅速产生耐药性,治疗效果有限。鉴于此,我们的工作旨在探索缓解恶劣条件的策略。我们采用系统的结构优化工艺,在现有pi的基础上设计合成了新的化合物BC12-3。采用JFCR39 COMPARE法测定其对39种特征性癌细胞的细胞毒活性,采用CCK-8法测定BC12-3的IC50值。流式细胞术检测细胞周期分布及凋亡情况,western blotting检测BC12-3抗肿瘤机制。在异种移植模型中评估BC12-3和硼替佐米(BTZ)的体内疗效和安全性。ADMET计算分析估计了这两种抑制剂的生物安全性。结果表明,BC12-3在体外表现出强大的广谱抗肿瘤活性,特别是对MM细胞;这种效果是通过选择性抑制蛋白酶体活性的β5亚基来实现的。BC12-3主要通过G2/M期细胞周期阻滞和诱导凋亡抑制MM细胞生长,相关分子途径证实了这些现象。体内研究表明,BC12-3具有明显的抑制肿瘤生长的作用,其疗效与标准治疗药物BTZ相当。此外,该新化合物显示出良好的安全性。因此,BC12-3有望成为治疗MM的一种新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Medical Oncology
Medical Oncology 医学-肿瘤学
CiteScore
4.20
自引率
2.90%
发文量
259
审稿时长
1.4 months
期刊介绍: Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信