Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor(HR)-positive advanced breast cancer. Circulating tumor DNA(ctDNA) has been allowed for the a...Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor(HR)-positive advanced breast cancer. Circulating tumor DNA(ctDNA) has been allowed for the assessment of the genomic profiles of patients with advanced cancer. We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2(HER-2)-negative metastatic breast cancer patients.Methods: In this open-label, multicohort, prospective study, patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA: 1) activation of the phosphatidylinositol-3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR) signaling pathway preferred mTOR inhibitor combined with endocrine therapy;2) estrogen receptor 1(ESR1) mutation preferred fulvestrant;3) HER-2 mutations preferred pyrotinib;and 4) no actionable mutations received treatment according to the clinical situation. In all cohorts, patients were divided into compliance group and violation group. The primary outcome measure was progression-free survival(PFS), and the secondary outcome measure was overall survival(OS).Results: In all cohorts, the combined median PFS was 4.9 months, and median PFS for the compliance and violation groups was 6.0 and 3.0 months, respectively [P=0.022, hazard ratio(HR)=0.57]. Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group(P=0.023, HR=0.55). Among the patients with HER-2 mutations, the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group(P=0.011, HR=0.20). There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation.Conclusions: The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS. Next-generation sequencing(NGS) detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.展开更多
背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者...背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者的心脏毒性,筛选易感人群,探讨心脏毒性与自噬相关基因多态性的相关性。方法在2450例I–III期TNBC患者中,有147例纳入了本研究。大多数患者在化疗周期前进行心电图(electrocardiography,ECG)检查,并根据临床需要进行超声心动图(echocardiography,UCG)检查。所有ECG和UCG资料均由阜外医院国家心血管病中心的心血管专家重新评判。根据美国国家生物技术信息中心数据库和癌症体细胞突变目录数据库,我们筛选了25个与自噬相关的单核苷酸多态性(single nucleotide polymorphisms,SNPs),并对147例TNBC患者进行了基因分型。采用配对样本T检验、卡方检验和logistic回归模型进行分析。结果每个化疗周期后,只有46(31.3%)例患者的ECG完全正常。在接受UCG的16例患者中,有2(12.5%)例患者左心室射血分数可逆性下降。使用蒽环类药物和过量饮酒是ECG异常的危险因素。随着化疗的持续,心率逐渐增加。蒽环类药物与QRS期持续异常有关(P=0.043)。我们对25个与自噬有关的SNP进行基因分型后发现,自噬相关基因13(ATG13)rs10838611的G等位基因与ECG异常显著相关(优势比=2.258,95%置信区间:1.318–3.869;P=0.003)。结论化疗引起的ECG异常在真实世界中很常见。自噬相关单核苷酸多态性与化疗引起的心脏毒性相关,本研究为自噬是化疗所致心脏损害的原因提供了新的证据。展开更多
Background:CDK4/6 inhibitors(CDK4/6i)have shown promising results in the treatment of hormone receptor‐positive(HR+)metastatic breast cancer(MBC)when combined with endocrine therapy(ET).It is crucial to evaluate the ...Background:CDK4/6 inhibitors(CDK4/6i)have shown promising results in the treatment of hormone receptor‐positive(HR+)metastatic breast cancer(MBC)when combined with endocrine therapy(ET).It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice,as well as to analyze the factors that can predict their outcomes.Methods:Patients with HR+MBC who received CDK4/6i‐based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression‐free survival(PFS).Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria(version 5.0).Results:This study included 344 patients,with a median PFS(mPFS)of 12.8 months(range:10.4–15.2 months).After adjustment,Cox multivariate regression analysis revealed that visceral metastasis(specifically liver and brain metastases),Eastern Cooperative Oncology Group Performance Status(ECOG PS)≥1,estrogen receptor≤80%,progesterone receptor≤10%,Ki‐67>30%,and treatment in later stages were significant factors associated with reduced PFS.Based on this,we created a prognostic nomogram and validated its performance,obtaining a C‐index of 0.714(95%confidence interval:0.640–0.787)as well as reliable calibration and clinical impact.The mPFS of CDK4/6i rechallenge was 7.7 months;for patients who initially discontinued CDK4/6i for reasons other than disease progression,CDK4/6i rechallenge still provided a mPFS of 11.4 months.The tolerability and safety of combining CDK4/6is with ET were manageable.Adverse events led to treatment discontinuation in 3.8%of patients.Neutropenia(29.1%),leukopenia(13.7%),and anemia(4.1%)were the primary grade 3/4 adverse reactions.Conclusions:This real‐world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+MBC.Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment.展开更多
Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the dir...Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies,direct action and bystander effect of cytotoxic drugs,and antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.ADCs have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2(HER2)-positive breast cancer,greatly improving the prognosis of breast cancer patients.Several ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant tumors.This review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.展开更多
Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Ca...Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Cardiac autophagy is an important mechanism of cardiotoxicity.This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC,screen the susceptible population,and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.Methods:From a total of 2450 stage I-III TNBC patients,147 met the inclusion criteria and finally recruited.Electro-cardiography(ECG)was performed before most chemotherapy cycles,and echocardiography(UCG)was performed according to clinical needs.All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease,Fuwai Hospital.According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database,we selected 25 single nucleotide polymorphisms(SNPs)related to autophagy and genotyped the 147 TNBC patients.Paired-sample T tests,Chi squared tests,and logistic regression models were employed for the analysis.Results:Only 46(31.3%)patients had normal ECG records after every chemotherapy cycle.Among the 16 patients who underwent UCG,2(12.5%)had a reversible decrease of left ventricular ejection fraction.The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities.With the continuation of chemotherapy,heart rate gradually increased.Anthracyclines were associated with QRS duration abnormalities(P=0.043).After genotyping for 25 autophagy-related SNPs,we found that the G allele of autophagy-related 13(ATG13)rs10838611 was significantly associated with ECG abnormalities(odds ratio=2.258,95%confidence interval=1.318-3.869;P=0.003).Conclusion:ECG abnormalities caused by chemotherapy are common in the real world.Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity,thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.展开更多
Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and pr...Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.展开更多
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 co...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 doxorubicininduced 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.展开更多
To the Editor:Cancer and cardiovascular(CV)disease are associated with the largest morbidity and mortality in the world,and they are related to each other through some common risk factors.
To the Editor:Cancer has been the leading cause of death worldwide and in China since 2010.[1]As advances are made in the treatment of cancer,the survival rate of cancer improves;at the same time,many cancer patients ...To the Editor:Cancer has been the leading cause of death worldwide and in China since 2010.[1]As advances are made in the treatment of cancer,the survival rate of cancer improves;at the same time,many cancer patients and cancer survivors suffer from cardiovascular disease(CVD)as a result of intense anticancer treatment.[2-4]To prevent and treat cardiovascular problems mediated by cancer treatments,a new medical discipline called cardiooncology was established.Although the field of cardiooncology has existed for 20 years,[5]its development in China is still in the early stages.展开更多
基金supported by grant from the CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2021I2M-1-014)。
文摘Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor(HR)-positive advanced breast cancer. Circulating tumor DNA(ctDNA) has been allowed for the assessment of the genomic profiles of patients with advanced cancer. We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2(HER-2)-negative metastatic breast cancer patients.Methods: In this open-label, multicohort, prospective study, patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA: 1) activation of the phosphatidylinositol-3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR) signaling pathway preferred mTOR inhibitor combined with endocrine therapy;2) estrogen receptor 1(ESR1) mutation preferred fulvestrant;3) HER-2 mutations preferred pyrotinib;and 4) no actionable mutations received treatment according to the clinical situation. In all cohorts, patients were divided into compliance group and violation group. The primary outcome measure was progression-free survival(PFS), and the secondary outcome measure was overall survival(OS).Results: In all cohorts, the combined median PFS was 4.9 months, and median PFS for the compliance and violation groups was 6.0 and 3.0 months, respectively [P=0.022, hazard ratio(HR)=0.57]. Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group(P=0.023, HR=0.55). Among the patients with HER-2 mutations, the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group(P=0.011, HR=0.20). There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation.Conclusions: The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS. Next-generation sequencing(NGS) detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.
文摘背景与目的越来越多的癌症患者死于心血管疾病。三阴性乳腺癌(triple-negative breast cancer,TNBC)可选的治疗方法有限,因此化疗引起的心脏毒性对该类患者非常重要。心脏自噬是心脏毒性的重要机制之一。本研究旨在研究化疗对TNBC患者的心脏毒性,筛选易感人群,探讨心脏毒性与自噬相关基因多态性的相关性。方法在2450例I–III期TNBC患者中,有147例纳入了本研究。大多数患者在化疗周期前进行心电图(electrocardiography,ECG)检查,并根据临床需要进行超声心动图(echocardiography,UCG)检查。所有ECG和UCG资料均由阜外医院国家心血管病中心的心血管专家重新评判。根据美国国家生物技术信息中心数据库和癌症体细胞突变目录数据库,我们筛选了25个与自噬相关的单核苷酸多态性(single nucleotide polymorphisms,SNPs),并对147例TNBC患者进行了基因分型。采用配对样本T检验、卡方检验和logistic回归模型进行分析。结果每个化疗周期后,只有46(31.3%)例患者的ECG完全正常。在接受UCG的16例患者中,有2(12.5%)例患者左心室射血分数可逆性下降。使用蒽环类药物和过量饮酒是ECG异常的危险因素。随着化疗的持续,心率逐渐增加。蒽环类药物与QRS期持续异常有关(P=0.043)。我们对25个与自噬有关的SNP进行基因分型后发现,自噬相关基因13(ATG13)rs10838611的G等位基因与ECG异常显著相关(优势比=2.258,95%置信区间:1.318–3.869;P=0.003)。结论化疗引起的ECG异常在真实世界中很常见。自噬相关单核苷酸多态性与化疗引起的心脏毒性相关,本研究为自噬是化疗所致心脏损害的原因提供了新的证据。
基金Hunan Provincial Natural Science Foundation of China,Grant/Award Numbers:2023JJ60334,2023JJ60464,2024JJ6289Beijing Science and Technology Innovation Medical Development Foundation,Grant/Award Number:KC2023‐JX‐0082‐05The Climb Plan of Hunan Cancer Hospital,Grant/Award Numbers:QH2023006,ZX2021005。
文摘Background:CDK4/6 inhibitors(CDK4/6i)have shown promising results in the treatment of hormone receptor‐positive(HR+)metastatic breast cancer(MBC)when combined with endocrine therapy(ET).It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice,as well as to analyze the factors that can predict their outcomes.Methods:Patients with HR+MBC who received CDK4/6i‐based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression‐free survival(PFS).Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria(version 5.0).Results:This study included 344 patients,with a median PFS(mPFS)of 12.8 months(range:10.4–15.2 months).After adjustment,Cox multivariate regression analysis revealed that visceral metastasis(specifically liver and brain metastases),Eastern Cooperative Oncology Group Performance Status(ECOG PS)≥1,estrogen receptor≤80%,progesterone receptor≤10%,Ki‐67>30%,and treatment in later stages were significant factors associated with reduced PFS.Based on this,we created a prognostic nomogram and validated its performance,obtaining a C‐index of 0.714(95%confidence interval:0.640–0.787)as well as reliable calibration and clinical impact.The mPFS of CDK4/6i rechallenge was 7.7 months;for patients who initially discontinued CDK4/6i for reasons other than disease progression,CDK4/6i rechallenge still provided a mPFS of 11.4 months.The tolerability and safety of combining CDK4/6is with ET were manageable.Adverse events led to treatment discontinuation in 3.8%of patients.Neutropenia(29.1%),leukopenia(13.7%),and anemia(4.1%)were the primary grade 3/4 adverse reactions.Conclusions:This real‐world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+MBC.Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment.
基金The study was supported by the grants from the National Natural Science Foundation of China(No.81874122)the Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(No.2017-I2M-3-004)。
文摘Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies,direct action and bystander effect of cytotoxic drugs,and antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.ADCs have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2(HER2)-positive breast cancer,greatly improving the prognosis of breast cancer patients.Several ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant tumors.This review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.
基金supported by the National Natural Science Foundation of China(No.81472453).
文摘Background:An increasing number of cancer patients die of cardiovascular diseases.The cardiotoxicity of chemo-therapy is particularly important in triple-negative breast cancer(TNBC)with limited therapeutic options.Cardiac autophagy is an important mechanism of cardiotoxicity.This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC,screen the susceptible population,and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.Methods:From a total of 2450 stage I-III TNBC patients,147 met the inclusion criteria and finally recruited.Electro-cardiography(ECG)was performed before most chemotherapy cycles,and echocardiography(UCG)was performed according to clinical needs.All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease,Fuwai Hospital.According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database,we selected 25 single nucleotide polymorphisms(SNPs)related to autophagy and genotyped the 147 TNBC patients.Paired-sample T tests,Chi squared tests,and logistic regression models were employed for the analysis.Results:Only 46(31.3%)patients had normal ECG records after every chemotherapy cycle.Among the 16 patients who underwent UCG,2(12.5%)had a reversible decrease of left ventricular ejection fraction.The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities.With the continuation of chemotherapy,heart rate gradually increased.Anthracyclines were associated with QRS duration abnormalities(P=0.043).After genotyping for 25 autophagy-related SNPs,we found that the G allele of autophagy-related 13(ATG13)rs10838611 was significantly associated with ECG abnormalities(odds ratio=2.258,95%confidence interval=1.318-3.869;P=0.003).Conclusion:ECG abnormalities caused by chemotherapy are common in the real world.Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity,thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.
基金This work was supported by‘National Natural Science Foundation of China’(Grant Number:81874122)‘CAMS Initiative for Innovative Medicine’(Grant Number:2017-I2M-3-004)‘Major Project of the Beijing Municipal Science and Technology Commission’(Grant Number:D161100000816004).
文摘Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.
基金supported by the National Natural Science Foundation of China (81871095 and 82170873)the National Key R&D Program of China (2018YFC2000304)+1 种基金the Tsinghua Precision Medicine Foundation (10001020132, China)the Tsinghua University Spring Breeze Fund (20211080005, China)。
文摘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 doxorubicininduced 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.
基金This work was supported by grants from Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-014)National Natural Science Foundation of China(No.82172875).
文摘To the Editor:Cancer and cardiovascular(CV)disease are associated with the largest morbidity and mortality in the world,and they are related to each other through some common risk factors.
文摘To the Editor:Cancer has been the leading cause of death worldwide and in China since 2010.[1]As advances are made in the treatment of cancer,the survival rate of cancer improves;at the same time,many cancer patients and cancer survivors suffer from cardiovascular disease(CVD)as a result of intense anticancer treatment.[2-4]To prevent and treat cardiovascular problems mediated by cancer treatments,a new medical discipline called cardiooncology was established.Although the field of cardiooncology has existed for 20 years,[5]its development in China is still in the early stages.
