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Theranostics 2020; 10(25):11622-11636. doi:10.7150/thno.47533 This issue Cite

Research Paper

Targeting BCL10 by small peptides for the treatment of B cell lymphoma

Wei Bao^1,2#, Chenxia Sun^1,2#, Xiaochen Sun^1,2, Miaoxia He³, Haolan Yu^1,2, Wenfen Yan^1,2, Fuping Wen^1,2, Liang Zhang^2,4,5✉, Chenghua Yang^1,2✉

1. Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China, 200433.
2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China, 200031.
3. Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China, 200433.
4. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, China, 100101.
5. Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, P.R. China.
#These authors contributed equally to this work.

✉ Corresponding authors: C. Yang, E-mail: chenghua-yangcom; and L. Zhang, E-mail: zhangliang01ac.cn.

Abstract

Rationale: Constitutive activation of the NF-κB signalling pathway plays a pivotal role in the pathogenesis of activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCLs), the most aggressive and chemoresistant form of DLBCL. In ABC-DLBCLs, the CARMA1-BCL10 (CB) complex forms a filamentous structure and functions as a supramolecular organizing centre (CB-SMOC) that is required for constitutive NF-κB activation, making it an attractive drug target for ABC-DLBCL treatment. However, a pharmaceutical approach targeting CB-SMOC has been lacking. Here, we developed Bcl10 peptide inhibitors (BPIs) that specifically target the BCL10 filamentation process.

Methods: Electron microscopy and immunofluorescence imaging were used to visualize the effect of the BPIs on the BCL10 filamentation process. The cytotoxicity of the tested BPIs was evaluated in DLBCL cell lines according to cell proliferation assays. Different in vitro experiments (pharmacokinetics, immunoprecipitation, western blotting, annexin V and PI staining) were conducted to determine the functional mechanisms of the BPIs. The in vivo therapeutic effect of the BPIs was examined in different xenograft DLBCL mouse models. Finally, Ki67 and TUNEL staining and histopathology analysis were used to evaluate the antineoplastic mechanisms and systemic toxicity of the BPIs.

Results: We showed that these BPIs can effectively disrupt the BCL10 filamentation process, destabilize BCL10 and suppress NF-κB signalling in ABC-DLBCL cells. By examining a panel of DLBCL cell lines, we found that these BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL cells by inducing apoptosis and cell cycle arrest. Moreover, by converting the BPIs to acquire a D-retro inverso (DRI) configuration, we developed DRI-BPIs with significantly improved intracellular stability and unimpaired BPI activity. These DRI-BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL tumors in mouse xenograft models without eliciting discernible adverse effects.

Conclusion: We developed novel BPIs to target the BCL10 filamentation process and demonstrated that targeting BCL10 by BPIs is a potentially safe and effective pharmaceutical approach for the treatment of ABC-DLBCL and other CB-SMOC-dependent malignancies.

Keywords: Bcl10, diffuse large B-cell lymphoma (DLBCL), Bcl10 peptide inhibitors (BPIs), NF-κB, CARMA1-BCL10 supramolecular organizing centre (CB-SMOC)

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