Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth

Li, Mingchuan; Sala, Valentina; Santis, Maria Chiara De; Cimino, James J.; Cappello, Paola; Pianca, Nicola; Bona, Anna Di; Margaria, Jean Piero; Martini, Miriam; Lazzarini, Edoardo; Pirozzi, Flora; Rossi, Luca; Franco, Irene; Bornbaum, Julia; Heger, Jacqueline; Rohrbach, Susanne; Perino, Alessia; Tocchetti, Carlo G.; Lima, Bráulio Henrique Freire; Teixeira, Mauro Martins; Porporato, Paolo E.; Schulz, Rainer; Angelini, Annalisa; Sandri, Marco; Ameri, Pietro; Sciarretta, Sebastiano; Lima-Júnior, Roberto César Pereira; Mongillo, Marco; Zaglia, Tania; Morello, Fulvio; Novelli, Francesco; Hirsch, Emilio; Ghigo, Alessandra

doi:10.1161/circulationaha.117.030352

Cited by 147 publications

(126 citation statements)

References 51 publications

(79 reference statements)

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“…Combining other drugs with Dox is a feasible strategy to enhance antitumor efficacy while avoiding unacceptable toxicity. 28 In the present study, our data showed that BAA attenuated Dox-induced cardiotoxicity in H9c2 cells in vitro and in zebrafish in vivo (Figure 1 and 4). The results demonstrated that sildenafil enhanced the chemotherapeutic efficacy of Dox while simultaneously provided the cardioprotective benefit.…”

Section: Er Stress Inhibitor 4-pba Compromised the Synergistic Antisupporting

confidence: 63%

“…27 A quite recent study indicated that PI3Kγ inhibition could simultaneously prevent cardiotoxicity and reduce tumor growth under Dox treatment. 28 In the present study, our data showed that BAA attenuated Dox-induced cardiotoxicity in H9c2 cells in vitro and in zebrafish in vivo (Figure 1 and 4). Moreover, BAA potentiates the antitumor activity under Dox treatment ( Figure 5).…”

Section: Er Stress Inhibitor 4-pba Compromised the Synergistic Antisupporting

confidence: 63%

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A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells

Zhang

Deng

Zhou

et al. 2018

J of Cellular Biochemistry

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Doxorubicin (Dox) is a well‐known chemotherapeutic agent used in the treatment of various cancers. However, Dox‐induced cardiotoxicity limits its further clinical use. We have previously reported a small molecular named biotin‐conjugated ADTM analog (BAA) that exhibits cytoprotective effects against oxidative stress–induced cell injury in cardiomyoblast H9c2 cells. Here, the protective effects of BAA, indexed by attenuation of the cardiotoxicity induced by Dox as well as synergistic antitumor activity that increases the chemotherapeutic efficacy of Dox were investigated. Our results demonstrated that BAA significantly ameliorated Dox‐induced toxicity in the H9c2 cells and zebrafish models. In addition, BAA attenuated Dox‐induced endoplasmic reticulum (ER) stress in H9c2 cells. An ER stress inhibitor, 4‐phenylbutyric acid, reversed the protective effect of BAA in H9c2 cells. In contrast, in human breast tumor MDA‐MB‐231 cells, BAA significantly enhanced Dox‐induced cytotoxicity through upregulating Dox‐induced ER stress response. Taken together, our findings indicate that Dox combined with BAA can significantly enhance its antitumor activity in breast cancer cells and reduce its cardiotoxicity, at least in part, by mediating ER stress activation.

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Section: Er Stress Inhibitor 4-pba Compromised the Synergistic Antisupporting

confidence: 63%

Section: Er Stress Inhibitor 4-pba Compromised the Synergistic Antisupporting

confidence: 63%

A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells

Zhang

Deng

Zhou

et al. 2018

J of Cellular Biochemistry

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“…Extracellular edema and fibrosis are commonly observed during several cardiac diseases including heart failure (29,30,37). DOX treatment has previously been shown to induce fibrosis in the heart (19,21). We next assessed myocardial collagen deposition in mice treated with DOX30 on Day 10 post-treatment using PicroSirius Red staining (Figure 4).…”

Section: Fibrosis Is Reduced In Hearts Of Dox-treated Female P38 -/-mentioning

confidence: 99%

“…The pathophysiological mechanisms of DOX-induced cardiotoxicity remain incompletely understood. Accumulating evidence implicates genotoxic stress associated with DOX-mediated induction of double-strand DNA breaks through inhibition of topoisomerase 2 (48,50), oxidative stress due to increased generation of reactive oxygen species (ROS) and antioxidant depletion (12,13), inflammation (11,45), as well as mitochondrial and autophagy dysregulation (8,15,21), in DOX-induced cardiac injury, leading to cardiomyocyte dysfunction and cell death.…”

Section: Introductionmentioning

confidence: 99%

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

George

Kiss

Obaid

et al. 2020

Preprint

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BACKGROUND: The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38 and p38, remain uncharacterized. OBJECTIVES: To determine the potential cardioprotective effects of p38 and p38 genetic deletion in mice subjected to acute DOX treatment. METHODS: Male and female wild-type (WT), p38 -/-, p38 -/-and p38 -/- -/-mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining.Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTS: Significantly improved survival was observed in p38 -/-female mice post-DOX relative to WT females, but not in p38 -/-or p38 -/- -/-male or female mice. The improved survival in DOX-treated p38 -/-females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38 -/-females. CONCLUSIONS: p38 plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38 targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. NEW AND NOTEWORTHY:This study for the first time identifies the roles of the alternative p38 and p38 MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38 systemic deletion did not affect DOX-cardiotoxicity, p38 systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38-/-females and autophagy was increased.

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“…Professor Carlo Gabriele Tocchetti (Naples, Italy) further deepened the concept about the importance of immunology in cardio-oncology: 97 not only can immunologic pathways be exploited to fight cancer 98 and predict the response to anti-cancer therapies 99 but also they are involved in the development of cardiotoxicity. 100 Professor Dirk Brutsaert (Antwerp, Belgium) discussed how an impairment of the endothelium could influence the progress of HF and cancer. According to him, the endothelium has haemodynamic, mechanical, and biochemical sensors for several molecules like proteins, microvesicles, peptides, and microRNA.…”

Section: Treatment Of Cardiotoxicity and New Frontiersmentioning

confidence: 99%

Recent advances in cardio‐oncology: a report from the ‘Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019’

et al. 2019

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While anti-cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio-oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio-oncology service, the collaboration among cardio-oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti-cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment.

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Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth

Abstract: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.

Cited by 147 publications

References 51 publications

A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells

A novel agent attenuates cardiotoxicity and improves antitumor activity of doxorubicin in breast cancer cells

p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

Recent advances in cardio‐oncology: a report from the ‘Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019’

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