Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling
Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was red...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523001090 |
| _version_ | 1797791917840269312 |
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| author | Kezheng Peng Chenye Zeng Yuqi Gao Binliang Liu Liyuan Li Kang Xu Yuemiao Yin Ying Qiu Mingkui Zhang Fei Ma Zhao Wang |
| author_facet | Kezheng Peng Chenye Zeng Yuqi Gao Binliang Liu Liyuan Li Kang Xu Yuemiao Yin Ying Qiu Mingkui Zhang Fei Ma Zhao Wang |
| author_sort | Kezheng Peng |
| collection | DOAJ |
| description | Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis. |
| first_indexed | 2024-03-13T02:25:37Z |
| format | Article |
| id | doaj.art-f226587f8e5c4faeb0b928e0fcde17e1 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-13T02:25:37Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-f226587f8e5c4faeb0b928e0fcde17e12023-06-30T04:21:59ZengElsevierActa Pharmaceutica Sinica B2211-38352023-06-0113626802700Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodelingKezheng Peng0Chenye Zeng1Yuqi Gao2Binliang Liu3Liyuan Li4Kang Xu5Yuemiao Yin6Ying Qiu7Mingkui Zhang8Fei Ma9Zhao Wang10The Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaThe Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaThe Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaThe Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaThe Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaThe Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaSchool of Medicine, Tsinghua University, Beijing 100084, ChinaDepartment of Cardiac Surgery, First Hospital of Tsinghua University, Beijing 100016, ChinaDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, ChinaThe Ministry of Education Key Laboratory of Protein Science, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Corresponding author.Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.http://www.sciencedirect.com/science/article/pii/S2211383523001090SIRT6DoxorubicinCardiotoxicityAntitumor efficacyEllagic acidMitochondrial homeostasis |
| spellingShingle | Kezheng Peng Chenye Zeng Yuqi Gao Binliang Liu Liyuan Li Kang Xu Yuemiao Yin Ying Qiu Mingkui Zhang Fei Ma Zhao Wang Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling Acta Pharmaceutica Sinica B SIRT6 Doxorubicin Cardiotoxicity Antitumor efficacy Ellagic acid Mitochondrial homeostasis |
| title | Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling |
| title_full | Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling |
| title_fullStr | Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling |
| title_full_unstemmed | Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling |
| title_short | Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling |
| title_sort | overexpressed sirt6 ameliorates doxorubicin induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling |
| topic | SIRT6 Doxorubicin Cardiotoxicity Antitumor efficacy Ellagic acid Mitochondrial homeostasis |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523001090 |
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