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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

APS reverses the doxorubicin-induced oxidative stress and apoptosis of cardiomyocytes. (a) DHE staining of control NRVMs, doxorubicin-treated (1 μM) NRVMs, and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4, **P < 0.01). (b) Cardiomyocyte apoptosis as detected by TUNEL in control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (c) Cardiomyocyte apoptosis as detected by DNA laddering for control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (d) APS suppressed doxorubicin-induced caspase 3 and caspase 9 activation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3) (##P < 0.01 versus control group, *P < 0.05 versus the doxorubicin-treated group, and **P < 0.01 versus the doxorubicin-treated group).
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fig3: APS reverses the doxorubicin-induced oxidative stress and apoptosis of cardiomyocytes. (a) DHE staining of control NRVMs, doxorubicin-treated (1 μM) NRVMs, and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4, **P < 0.01). (b) Cardiomyocyte apoptosis as detected by TUNEL in control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (c) Cardiomyocyte apoptosis as detected by DNA laddering for control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (d) APS suppressed doxorubicin-induced caspase 3 and caspase 9 activation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3) (##P < 0.01 versus control group, *P < 0.05 versus the doxorubicin-treated group, and **P < 0.01 versus the doxorubicin-treated group).

Mentions: Cell viability assays were performed using doxorubicin-treated NRVMs. As shown in Figure 2(a), doxorubicin treatment reduced cell viability in a dose-dependent manner compared with the control; 0.1 μM doxorubicin treatment led to 20% decreased cell viability. Similarly, TUNEL assay (Figure 2(b)) verified that doxorubicin triggered apoptosis in a dose-dependent manner. Moreover, to explore the underlying mechanisms of cardiotoxicity induced by doxorubicin, cell survival and apoptosis-related signaling proteins such as caspase 3 and p38MAPK were detected. The levels of active (cleaved) caspase 3 and phosphorylated p38MAPK were significantly increased in a concentration-dependent manner in cardiomyocytes treated for 24 h with doxorubicin (Figure 2(c)). Moreover, doxorubicin led to elevated ROS generation in the hearts of C57BL/6J mice and cultured NRVMs (Figure 3(a)). These results indicate that doxorubicin could induce cardiotoxicity via oxidative stress and apoptosis.


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)

APS reverses the doxorubicin-induced oxidative stress and apoptosis of cardiomyocytes. (a) DHE staining of control NRVMs, doxorubicin-treated (1 μM) NRVMs, and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4, **P < 0.01). (b) Cardiomyocyte apoptosis as detected by TUNEL in control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (c) Cardiomyocyte apoptosis as detected by DNA laddering for control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (d) APS suppressed doxorubicin-induced caspase 3 and caspase 9 activation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3) (##P < 0.01 versus control group, *P < 0.05 versus the doxorubicin-treated group, and **P < 0.01 versus the doxorubicin-treated group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: APS reverses the doxorubicin-induced oxidative stress and apoptosis of cardiomyocytes. (a) DHE staining of control NRVMs, doxorubicin-treated (1 μM) NRVMs, and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4, **P < 0.01). (b) Cardiomyocyte apoptosis as detected by TUNEL in control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (c) Cardiomyocyte apoptosis as detected by DNA laddering for control and doxorubicin-treated (1 μM) NRVMs and NRVMs pretreated with APS (50 μg/mL) followed by doxorubicin treatment (n = 4). (d) APS suppressed doxorubicin-induced caspase 3 and caspase 9 activation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3) (##P < 0.01 versus control group, *P < 0.05 versus the doxorubicin-treated group, and **P < 0.01 versus the doxorubicin-treated group).
Mentions: Cell viability assays were performed using doxorubicin-treated NRVMs. As shown in Figure 2(a), doxorubicin treatment reduced cell viability in a dose-dependent manner compared with the control; 0.1 μM doxorubicin treatment led to 20% decreased cell viability. Similarly, TUNEL assay (Figure 2(b)) verified that doxorubicin triggered apoptosis in a dose-dependent manner. Moreover, to explore the underlying mechanisms of cardiotoxicity induced by doxorubicin, cell survival and apoptosis-related signaling proteins such as caspase 3 and p38MAPK were detected. The levels of active (cleaved) caspase 3 and phosphorylated p38MAPK were significantly increased in a concentration-dependent manner in cardiomyocytes treated for 24 h with doxorubicin (Figure 2(c)). Moreover, doxorubicin led to elevated ROS generation in the hearts of C57BL/6J mice and cultured NRVMs (Figure 3(a)). These results indicate that doxorubicin could induce cardiotoxicity via oxidative stress and apoptosis.

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