Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells
Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient ou...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.636373/full |
| _version_ | 1818576020139147264 |
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| author | Hongyan Ma Hongyan Ma Hongyan Ma Qizhang Li Qizhang Li Jing Wang Jing Wang Jing Wang Jing Pan Jing Pan Jing Pan Zhengding Su Zhengding Su Sen Liu Sen Liu Sen Liu |
| author_facet | Hongyan Ma Hongyan Ma Hongyan Ma Qizhang Li Qizhang Li Jing Wang Jing Wang Jing Wang Jing Pan Jing Pan Jing Pan Zhengding Su Zhengding Su Sen Liu Sen Liu Sen Liu |
| author_sort | Hongyan Ma |
| collection | DOAJ |
| description | Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer. |
| first_indexed | 2024-12-15T00:48:41Z |
| format | Article |
| id | doaj.art-5094b02e3f8f43c0b270f738a7bf43fe |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-15T00:48:41Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-5094b02e3f8f43c0b270f738a7bf43fe2022-12-21T22:41:28ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-03-011110.3389/fonc.2021.636373636373Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor CellsHongyan Ma0Hongyan Ma1Hongyan Ma2Qizhang Li3Qizhang Li4Jing Wang5Jing Wang6Jing Wang7Jing Pan8Jing Pan9Jing Pan10Zhengding Su11Zhengding Su12Sen Liu13Sen Liu14Sen Liu15National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, ChinaInstitute of Biomedical and Pharmaceutical Sciences, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, ChinaHubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, ChinaInstitute of Biomedical and Pharmaceutical Sciences, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, ChinaInstitute of Biomedical and Pharmaceutical Sciences, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, ChinaHubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, ChinaInstitute of Biomedical and Pharmaceutical Sciences, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, ChinaHubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, ChinaInstitute of Biomedical and Pharmaceutical Sciences, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, ChinaInstitute of Biomedical and Pharmaceutical Sciences, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, ChinaHubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang, ChinaPersonized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.https://www.frontiersin.org/articles/10.3389/fonc.2021.636373/fulldual inhibitorornithine decarboxylase 1 (ODC)A1ARpolyamine pathwaycyclic AMP (cAMP) pathway |
| spellingShingle | Hongyan Ma Hongyan Ma Hongyan Ma Qizhang Li Qizhang Li Jing Wang Jing Wang Jing Wang Jing Pan Jing Pan Jing Pan Zhengding Su Zhengding Su Sen Liu Sen Liu Sen Liu Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells Frontiers in Oncology dual inhibitor ornithine decarboxylase 1 (ODC) A1AR polyamine pathway cyclic AMP (cAMP) pathway |
| title | Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells |
| title_full | Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells |
| title_fullStr | Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells |
| title_full_unstemmed | Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells |
| title_short | Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells |
| title_sort | dual inhibition of ornithine decarboxylase and a1 adenosine receptor efficiently suppresses breast tumor cells |
| topic | dual inhibitor ornithine decarboxylase 1 (ODC) A1AR polyamine pathway cyclic AMP (cAMP) pathway |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.636373/full |
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