PI3Kγ inhibition protects from anthracycline-induced heart failure and reduces tumor growth

Li, M.; Sala, Valentina; Santis, Maria Chiara De; Cimino, James J.; Cappello, Paola; Pianca, Nicola; Martini, Miriam; Lazzarini, Edoardo; Pirozzi, Flora; Tocchetti, Carlo G.; Sandri, Marco; Ameri, Pietro; Sciarretta, S.; Mongillo, Marco; Zaglia, Tania; Morello, Fulvio; Novelli, Francesco; Hirsch, Emilio; Ghigo, Alessandra

doi:10.1016/j.vph.2017.12.035

Cited by 3 publications

(3 citation statements)

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“…Our data indicate that IL-12p35 KO promoted Mø1 differentiation and Mø1-related inflammatory cytokine expression but inhibited Mø2 differentiation and Mø2-related inflammatory cytokine expression. We also found that DOX treatment inhibited Mø2 differentiation, which is consistent with a recent study [ 4 ]. However, the present study found that IL-12p35 KO further reduced Mø2 differentiation, which is in contrast to the findings of a previous article [ 21 ], potentially due to the use of different experimental models.…”

Section: Discussionsupporting

confidence: 93%

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Interleukin-12p35 Knock Out Aggravates Doxorubicin-Induced Cardiac Injury and Dysfunction by Aggravating the Inflammatory Response, Oxidative Stress, Apoptosis and Autophagy in Mice

Huang

et al. 2018

EBioMedicine

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Background Recent evidence has demonstrated that interleukin 12p35 knockout (IL-12p35 KO) is involved in cardiac diseases by regulating the inflammatory response. The involvement of inflammatory cells has also been observed in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate whether IL-12p35 KO affects DOX-induced cardiac injury and the underlying mechanisms. Methods First, the effect of DOX treatment on cardiac IL-12p35 expression was assessed. In addition, to investigate the effect of IL-12p35 KO on DOX-induced cardiac injury, IL-12p35 KO mice were treated with DOX. Because IL-12p35 is the mutual subunit of IL-12 and IL-35, to determine the cytokine that mediates the effect of IL-12p35 KO on DOX-induced cardiac injury, mice were given phosphate-buffered saline (PBS), mouse recombinant IL-12 (rIL-12) or rIL-35 before treatment with DOX. Results DOX treatment significantly increased the level of cardiac IL-12p35 expression. In addition, IL-12p35 KO mice exhibited higher serum and heart lactate dehydrogenase levels, higher serum and heart creatine kinase myocardial bound levels, and greater cardiac dysfunction than DOX-treated mice. Furthermore, IL-12p35 KO further increased M1 macrophage and decreased M2 macrophage differentiation, aggravated the imbalance of oxidants and antioxidants, and further activated the mitochondrial apoptotic pathway and endoplasmic reticulum stress autophagy pathway. Both rIL-12 and rIL-35 protected against DOX-induced cardiac injury by alleviating the inflammatory response, oxidative stress, apoptosis and autophagy. Conclusions IL-12p35 KO aggravated DOX-induced cardiac injury by amplifying the levels of inflammation, oxidative stress, apoptosis and autophagy. (234 words).

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Section: Discussionsupporting

confidence: 93%

“…Although the specific mechanisms remain unknown, the inflammatory response has been demonstrated to be closely related to DOX-induced cardiac injury [ 4 , 5 ]. Interleukins (ILs) are a type of cytokine closely related to the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-12p35 Knock Out Aggravates Doxorubicin-Induced Cardiac Injury and Dysfunction by Aggravating the Inflammatory Response, Oxidative Stress, Apoptosis and Autophagy in Mice

Huang

et al. 2018

EBioMedicine

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“…Brev and Dexra were treated after Dox injections. Survival was monitored daily and heart function was assessed by echocardiography, 3 weeks after the first injection of Dox (Li et al, 2018).…”

Section: Animal Experimental Protocolsmentioning

confidence: 99%

Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity

Sun²,

Yang³

et al. 2022

Front. Pharmacol.

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Aims: The broad-spectrum anticancer drug doxorubicin (Dox) is associated with a high incidence of cardiotoxicity, which severely affects the clinical application of the drug and patients’ quality of life. Here, we assess how Dox modulates myocardial energy and contractile function and this could aid the development of relevant protective drugs.Methods: Mice were subjected to doxorubicin and breviscapine treatment. Cardiac function was analyzed by echocardiography, and Dox-mediated signaling was assessed in isolated cardiomyocytes. The dual cardio-protective and anti-tumor actions of breviscapine were assessed in mouse breast tumor models.Results: We found that Dox disrupts myocardial energy metabolism by decreasing glucose uptake and increasing fatty acid oxidation, leading to a decrease in ATP production rate, an increase in oxygen consumption rate and oxidative stress, and further energy deficits to enhance myocardial fatty acid uptake and drive DIC development. Interestingly, breviscapine increases the efficiency of ATP production and restores myocardial energy homeostasis by modulating the serotonin-glucose-myocardial PI3K/AKT loop, increasing glucose utilization by the heart and reducing lipid oxidation. It enhances mitochondrial autophagy via the PINK1/Parkin pathway, eliminates damaged mitochondrial accumulation caused by Dox, reduces the degree of cardiac fibrosis and inflammation, and restores cardiac micro-environmental homeostasis. Importantly, its low inflammation levels reduce myeloid immunosuppressive cell infiltration, and this effect is synergistic with the anti-tumor effect of Dox.Conclusion: Our findings suggest that disruption of the cardiac metabolic network by Dox is an important driver of its cardiotoxicity and that serotonin is an important regulator of myocardial glucose and lipid metabolism. Myocardial energy homeostasis and timely clearance of damaged mitochondria synergistically contribute to the prevention of anthracycline-induced cardiotoxicity and improve the efficiency of tumor treatment.

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Potential targets for intervention against doxorubicin-induced cardiotoxicity based on genetic studies: a systematic review of the literature

Chen

Huang

Shi

et al. 2020

Journal of Molecular and Cellular Cardiology

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PI3Kγ inhibition protects from anthracycline-induced heart failure and reduces tumor growth

Cited by 3 publications

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Interleukin-12p35 Knock Out Aggravates Doxorubicin-Induced Cardiac Injury and Dysfunction by Aggravating the Inflammatory Response, Oxidative Stress, Apoptosis and Autophagy in Mice

Interleukin-12p35 Knock Out Aggravates Doxorubicin-Induced Cardiac Injury and Dysfunction by Aggravating the Inflammatory Response, Oxidative Stress, Apoptosis and Autophagy in Mice

Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity

Potential targets for intervention against doxorubicin-induced cardiotoxicity based on genetic studies: a systematic review of the literature

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