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Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Cao Y, Ruan Y, Shen T, Huang X, Li M, Yu W, Zhu Y, Man Y, Wang S, Li J - Oxid Med Cell Longev (2014)

Bottom Line: Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation.Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction.In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

View Article: PubMed Central - PubMed

Affiliation: The Fifth Clinical Hospital of Peking University, Health Science Center, Beijing 100730, China ; Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health of China, Beijing 100730, China.

ABSTRACT

Background: Doxorubicin, a potent chemotherapeutic agent, is associated with acute and chronic cardiotoxicity, which is cumulatively dose-dependent. Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation. However, whether APS could ameliorate chemotherapy-induced cardiotoxicity is not understood. Here, we investigated the protective effects of APS on doxorubicin-induced cardiotoxicity and elucidated the underlying mechanisms of the protective effects of APS.

Methods: We analyzed myocardial injury in cancer patients who underwent doxorubicin chemotherapy and generated a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, DNA laddering, and Western blotting were performed to observe cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.

Results: Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction. Doxorubicin reduced cardiomyocyte viability and induced C57BL/6J mouse heart failure with concurrent elevated ROS generation and apoptosis, which, however, was attenuated by APS treatment. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

Conclusions: These results demonstrate that APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

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Related in: MedlinePlus

Increased levels of serum myocardial enzymes accompanied by heart dysfunction in cancer patients treated with doxorubicin. The average left ventricle ejection fraction (LVEF %) (a), median serum cTNT (b), and CK-MB (c) levels before and after chemotherapy (n = 63, **P < 0.01, ***P < 0.001).
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fig1: Increased levels of serum myocardial enzymes accompanied by heart dysfunction in cancer patients treated with doxorubicin. The average left ventricle ejection fraction (LVEF %) (a), median serum cTNT (b), and CK-MB (c) levels before and after chemotherapy (n = 63, **P < 0.01, ***P < 0.001).

Mentions: Clinical data from 206 cancer patients who had no comorbidities, such as diabetes, hypertension, and ischemic heart disease, and underwent initial doxorubicin-based chemotherapy (a cumulative dose of 450–600 mg/m2) were retrospectively analyzed. Fifteen patients who had no history of cardiovascular disease but an abnormal electrocardiograph (ECG) before chemotherapy were excluded from the database. A total of 63 patients (30.6% of total patients) who had a normal ECG before chemotherapy and an abnormal ECG after chemotherapy had a normal baseline LVEF 65.1 ± 4.5% and a final value less than 53.2 ± 7.4% after doxorubicin therapy (Figure 1(a)). Serial determinations of cardiac enzymes (cTNT, CK-MB) were performed. After chemotherapy, the median serum cTNT level increased from 0.04 ng/mL (75%—CI: 0.025–0.072 ng/mL) to 0.15 ng/mL (75%—CI: 0.13–0.21 ng/mL) for 63 patients (Figure 1(b)), and the median serum CK-MB level was elevated from 2.1 ng/mL (75%—CI: 1.29–2.49 ng/mL) to 5.73 ng/mL (75%—CI: 5.17–6.28 ng/mL) (Figure 1(c)). The average serum cTNT and CK-MB levels exceeded the threshold for normal values (0.1 and 5.0 ng/mL, resp.) [14].


Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Cao Y, Ruan Y, Shen T, Huang X, Li M, Yu W, Zhu Y, Man Y, Wang S, Li J - Oxid Med Cell Longev (2014)

Increased levels of serum myocardial enzymes accompanied by heart dysfunction in cancer patients treated with doxorubicin. The average left ventricle ejection fraction (LVEF %) (a), median serum cTNT (b), and CK-MB (c) levels before and after chemotherapy (n = 63, **P < 0.01, ***P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4216718&req=5

fig1: Increased levels of serum myocardial enzymes accompanied by heart dysfunction in cancer patients treated with doxorubicin. The average left ventricle ejection fraction (LVEF %) (a), median serum cTNT (b), and CK-MB (c) levels before and after chemotherapy (n = 63, **P < 0.01, ***P < 0.001).
Mentions: Clinical data from 206 cancer patients who had no comorbidities, such as diabetes, hypertension, and ischemic heart disease, and underwent initial doxorubicin-based chemotherapy (a cumulative dose of 450–600 mg/m2) were retrospectively analyzed. Fifteen patients who had no history of cardiovascular disease but an abnormal electrocardiograph (ECG) before chemotherapy were excluded from the database. A total of 63 patients (30.6% of total patients) who had a normal ECG before chemotherapy and an abnormal ECG after chemotherapy had a normal baseline LVEF 65.1 ± 4.5% and a final value less than 53.2 ± 7.4% after doxorubicin therapy (Figure 1(a)). Serial determinations of cardiac enzymes (cTNT, CK-MB) were performed. After chemotherapy, the median serum cTNT level increased from 0.04 ng/mL (75%—CI: 0.025–0.072 ng/mL) to 0.15 ng/mL (75%—CI: 0.13–0.21 ng/mL) for 63 patients (Figure 1(b)), and the median serum CK-MB level was elevated from 2.1 ng/mL (75%—CI: 1.29–2.49 ng/mL) to 5.73 ng/mL (75%—CI: 5.17–6.28 ng/mL) (Figure 1(c)). The average serum cTNT and CK-MB levels exceeded the threshold for normal values (0.1 and 5.0 ng/mL, resp.) [14].

Bottom Line: Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation.Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction.In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

View Article: PubMed Central - PubMed

Affiliation: The Fifth Clinical Hospital of Peking University, Health Science Center, Beijing 100730, China ; Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health of China, Beijing 100730, China.

ABSTRACT

Background: Doxorubicin, a potent chemotherapeutic agent, is associated with acute and chronic cardiotoxicity, which is cumulatively dose-dependent. Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation. However, whether APS could ameliorate chemotherapy-induced cardiotoxicity is not understood. Here, we investigated the protective effects of APS on doxorubicin-induced cardiotoxicity and elucidated the underlying mechanisms of the protective effects of APS.

Methods: We analyzed myocardial injury in cancer patients who underwent doxorubicin chemotherapy and generated a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, DNA laddering, and Western blotting were performed to observe cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.

Results: Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction. Doxorubicin reduced cardiomyocyte viability and induced C57BL/6J mouse heart failure with concurrent elevated ROS generation and apoptosis, which, however, was attenuated by APS treatment. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

Conclusions: These results demonstrate that APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Show MeSH
Related in: MedlinePlus