The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin's lymphoma tumor growth by promoting apoptosis and autophagy.
The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin's lymphoma tumor growth by promoting apoptosis and autophagy.
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DOI：
10.1186/s12964-022-01031-x
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发表时间：
2023-01-23
影响因子：
8.4
通讯作者：
Feng, Jifeng
中科院分区：
文献类型：
--
作者：
Lv, Yan;Du, Yuxin;Li, Kening;Ma, Xiao;Wang, Juan;Du, Tongde;Ma, Yuxin;Teng, Yue;Tang, Weiyan;Ma, Rong;Wu, Jianqiu;Wu, Jianzhong;Feng, Jifeng
侵袭性 B 细胞非霍奇金淋巴瘤 (B-NHL) 患者在常规免疫化疗后经常出现耐药性和肿瘤复发，需要新的治疗方法。我们研究了 CBL0137 的抗肿瘤作用。在体外，通过 CCK-8 和集落形成测定评估细胞增殖。采用流式细胞术分析细胞周期进程、细胞凋亡、线粒体去极化和活性氧 (ROS) 产生。通过透射电子显微镜和mGFP-RFP-LC3测定检测自噬，并采用蛋白质印迹法检测参与细胞凋亡和自噬的蛋白。通过 RNA 测序来分析 CBL0137 处理 B-NHL 细胞系后的转录扰动。最后，在体内测试了CBL0137、利妥昔单抗及其组合的有效性和安全性。 CBL0137是一种小分子抗癌药物，对B-NHL具有显着的抗肿瘤作用。 CBL0137 将 FACT（促进染色质转录）复合物与染色质隔离，在 B-NHL 细胞中产生细胞毒性作用。此外，我们还发现了CBL0137新的抗癌机制。 CBL0137 通过 c-MYC/p53/p21 途径诱导细胞周期停滞在 S 期，从而抑制人 B-NHL 细胞增殖。此外，CBL0137 通过 ROS 介导的 PI3K/Akt/mTOR 和 MAPK 信号通路触发 ROS 生成并诱导 B-NHL 细胞凋亡和自噬。值得注意的是，CBL0137 和利妥昔单抗的组合可显着抑制皮下模型中的 B-NHL 肿瘤生长，这与体外细胞水平的结果一致。 CBL0137具有作为侵袭性B-NHL新方法的潜力，其与利妥昔单抗的组合可以为侵袭性B-NHL患者提供新的治疗选择。视频摘要 在线版本包含可在 10.1186/s12964-022-01031-x 获取的补充材料。
Aggressive B-cell non-Hodgkin’s lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed. We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo. CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro. CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL. Video Abstract The online version contains supplementary material available at 10.1186/s12964-022-01031-x.
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影响因子：
24.7
作者：
Frontzek, Fabian;Ziepert, Marita;Schmitz, Norbert
通讯作者：
Schmitz, Norbert
影响因子：
17.1
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
通讯作者：
Marshall GM
影响因子：
4
作者：
Belotserkovskaya, R;Reinberg, D
通讯作者：
Reinberg, D
影响因子：
13.3
作者：
Ginet, Vanessa;Puyal, Julien;Nahimana, Aimable
通讯作者：
Nahimana, Aimable
影响因子：
82.9
作者：
Chapuy B;Stewart C;Dunford AJ;Kim J;Kamburov A;Redd RA;Lawrence MS;Roemer MGM;Li AJ;Ziepert M;Staiger AM;Wala JA;Ducar MD;Leshchiner I;Rheinbay E;Taylor-Weiner A;Coughlin CA;Hess JM;Pedamallu CS;Livitz D;Rosebrock D;Rosenberg M;Tracy AA;Horn H;van Hummelen P;Feldman AL;Link BK;Novak AJ;Cerhan JR;Habermann TM;Siebert R;Rosenwald A;Thorner AR;Meyerson ML;Golub TR;Beroukhim R;Wulf GG;Ott G;Rodig SJ;Monti S;Neuberg DS;Loeffler M;Pfreundschuh M;Trümper L;Getz G;Shipp MA
通讯作者：
Shipp MA