Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis
BACKGROUND: Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin’s lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivit...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692258/ https://www.ncbi.nlm.nih.gov/pubmed/34956875 http://dx.doi.org/10.3389/fonc.2021.751904 |
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author | Ge, Xiaowen Du, Yiqun Chen, Jianfeng Zhu, Na Yao, Jiamei Zhang, Xin Wang, Na Sun, Yujing Gao, Feng Hu, Weiguo Hou, Yingyong |
author_facet | Ge, Xiaowen Du, Yiqun Chen, Jianfeng Zhu, Na Yao, Jiamei Zhang, Xin Wang, Na Sun, Yujing Gao, Feng Hu, Weiguo Hou, Yingyong |
author_sort | Ge, Xiaowen |
collection | PubMed |
description | BACKGROUND: Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin’s lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression. METHODS: Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The in vitro and in vivo experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH. RESULTS: We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues. CONCLUSIONS: Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy. |
format | Online Article Text |
id | pubmed-8692258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86922582021-12-23 Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis Ge, Xiaowen Du, Yiqun Chen, Jianfeng Zhu, Na Yao, Jiamei Zhang, Xin Wang, Na Sun, Yujing Gao, Feng Hu, Weiguo Hou, Yingyong Front Oncol Oncology BACKGROUND: Drug resistance remains a serious challenge to rituximab therapy in B-NHL (B cell non-Hodgkin’s lymphoma). CDC (complement-dependent cytotoxicity) has been proposed as a major antitumor mechanism of rituximab, and direct abrogation of CD59 function partially restores rituximab sensitivity with high efficacy. However, universal blockade of CD59 may have deleterious effects on normal cells. Sp1 regulates constitutive CD59 expression, whereas NF-κB and CREB regulate inducible CD59 expression. METHODS: Immunohistochemistry (IHC) assay was used to detect the expression levels of CD59 and other related molecules. Quantitative Real-time PCR (RT-PCR) analysis was used to explore the levels of transcripts in the original and resistant cells. We chose LY8 cells to test the effects of NF-κB and CBP/p300 inhibition on CD59 expression using flow cytometry (FACS). Immunoblotting analysis was employed to detect the effects of curcumin and POH. The in vitro and in vivo experiments were used to evaluate the toxicity and combined inhibitory effect on tumor cells of curcumin and POH. RESULTS: We demonstrated that herbal (curcumin and perillyl alcohol) blockade of NF-κB specifically suppresses the expression of inducible CD59 but not CD20, thus sensitizing resistant cells to rituximab-mediated CDC. Moreover, activation of NF-κB and CREB is highly correlated with CD59 expression in B-NHL tissues. CONCLUSIONS: Our findings suggest the potential of CD59 expression as a predictor of therapeutic efficacy of NF-κB inhibitors in clinical application as well as the rationality of a NF-κB inhibitor-rituximab regimen in B-NHL therapy. Frontiers Media S.A. 2021-12-08 /pmc/articles/PMC8692258/ /pubmed/34956875 http://dx.doi.org/10.3389/fonc.2021.751904 Text en Copyright © 2021 Ge, Du, Chen, Zhu, Yao, Zhang, Wang, Sun, Gao, Hu and Hou https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Ge, Xiaowen Du, Yiqun Chen, Jianfeng Zhu, Na Yao, Jiamei Zhang, Xin Wang, Na Sun, Yujing Gao, Feng Hu, Weiguo Hou, Yingyong Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis |
title | Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis |
title_full | Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis |
title_fullStr | Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis |
title_full_unstemmed | Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis |
title_short | Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis |
title_sort | herbal nf-κb inhibitors sensitize rituximab-resistant b lymphoma cells to complement-mediated cytolysis |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692258/ https://www.ncbi.nlm.nih.gov/pubmed/34956875 http://dx.doi.org/10.3389/fonc.2021.751904 |
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