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Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer

The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA...

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Autores principales: Pan, Di, Zhang, Wen, Zhang, Nenling, Xu, Yini, Chen, Yi, Peng, Jianqing, Chen, Yan, Zhang, Yanyan, Shen, Xiangchun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297828/
https://www.ncbi.nlm.nih.gov/pubmed/34305593
http://dx.doi.org/10.3389/fphar.2021.673432
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author Pan, Di
Zhang, Wen
Zhang, Nenling
Xu, Yini
Chen, Yi
Peng, Jianqing
Chen, Yan
Zhang, Yanyan
Shen, Xiangchun
author_facet Pan, Di
Zhang, Wen
Zhang, Nenling
Xu, Yini
Chen, Yi
Peng, Jianqing
Chen, Yan
Zhang, Yanyan
Shen, Xiangchun
author_sort Pan, Di
collection PubMed
description The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX–induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients.
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spelling pubmed-82978282021-07-23 Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer Pan, Di Zhang, Wen Zhang, Nenling Xu, Yini Chen, Yi Peng, Jianqing Chen, Yan Zhang, Yanyan Shen, Xiangchun Front Pharmacol Pharmacology The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX–induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients. Frontiers Media S.A. 2021-06-30 /pmc/articles/PMC8297828/ /pubmed/34305593 http://dx.doi.org/10.3389/fphar.2021.673432 Text en Copyright © 2021 Pan, Zhang, Zhang, Xu, Chen, Peng, Chen, Zhang and Shen. 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 Pharmacology
Pan, Di
Zhang, Wen
Zhang, Nenling
Xu, Yini
Chen, Yi
Peng, Jianqing
Chen, Yan
Zhang, Yanyan
Shen, Xiangchun
Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer
title Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer
title_full Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer
title_fullStr Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer
title_full_unstemmed Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer
title_short Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer
title_sort oxymatrine synergistically enhances doxorubicin anticancer effects in colorectal cancer
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297828/
https://www.ncbi.nlm.nih.gov/pubmed/34305593
http://dx.doi.org/10.3389/fphar.2021.673432
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