Natural compounds against doxorubicin‐induced cardiotoxicity: A review on the involvement of Nrf2/<scp>ARE</scp> signaling pathway

Yarmohammadi, Fatemeh; Rezaee, Ramin; Karimi, Gholamreza

doi:10.1002/ptr.6882

Cited by 81 publications

(76 citation statements)

References 158 publications

(222 reference statements)

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“…Furthermore, our results demonstrated that down regulation of p -Akt (Ser473)/Akt, p -mTOR/mTOR p -ULK1 (Ser757)/ULK1 and subsequent up-regulation of p -AMPKα/AMPK and p -ULK1 (Ser555)/ULK1 were observed in CuSO 4 -treated RAW264.7 cells. The canonical PI3K/Akt-mTOR signal transduction pathway has been identified to be the critical factor to adversely regulate autophagosome formation [ 24 ]. The PI3K/Akt signal transduction pathway controls mTOR activity [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: mtROS-mediated Akt/AMPK/mTOR pathway was involved in Copper-induced autophagy and it attenuates Copper-induced apoptosis in RAW264.7 mouse monocytes

et al. 2021

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Copper (Cu) is a trace element necessary in animals as well as human beings. However, excessive Cu is toxic to immunocytes, but the precise mechanism is largely unclear so far. This work was conducted aiming to examine the Cu-mediated autophagy mechanism together with its role in Cu toxicology in RAW264.7 cells. Here, we demonstrated that CuSO 4 reduced the cell viability depending on its dose. CuSO 4 could obviously increase autophagy in RAW264.7 cells. According to the obtained results, CuSO 4 induced autophagy through Akt/AMPK/mTOR pathway which characterized by down regulation of p -Akt (Ser473)/Akt, p -mTOR/mTOR, p -ULK1(Ser757)/ULK1 and subsequent up-regulation of p -AMPKα/AMPKα and p -ULK1(Ser555)/ULK1. Furthermore, CuSO 4 significantly induced the production of mitochondrial reactive oxygen species (mtROS). In addition, CuSO 4 -mediated apoptosis and autophagy might be suppressed through suppressing mtROS generation by exposure to Mito-TEMPO. Intriguingly, autophagy promotion with rapamycin could decrease the apoptosis and the inhibition of autophagy with knock down Atg5 could enhance the apoptosis induced by CuSO 4 . Moreover, our results suggested that mtROS is the original cause in CuSO 4 -induced apoptosis and autophagy. Additionally, CuSO 4 induced autophagy through mtROS-dependent Akt/AMPK/mTOR signalling pathwayin RAW264.7 cells. Moreover, autophagy activation might potentially generate a protection mechanism for improving CuSO 4 -induced RAW264.7 cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: mtROS-mediated Akt/AMPK/mTOR pathway was involved in Copper-induced autophagy and it attenuates Copper-induced apoptosis in RAW264.7 mouse monocytes

et al. 2021

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“…There are two main strategies under study to alleviate DOX cardiotoxicity: 1) structural modifications by pharmaceutical or chemical methods of the parent DOX, such as the synthesis of DOX analogues (idamycin and epirubicin) or development of new DOX formulations (liposome DOX); and 2) drug combinations being evaluated in pharmacological research. At present, dexrazoxane (ADR-529, ICRF-187), a cyclic derivative of ethylenediaminetetraacetic acid, is the only agent approved by the U.S. Food and Drug Administration (FDA) to reduce DOX-induced DIC ( Yarmohammadi et al, 2021 ). However, its clinical use has been restricted due to potential carcinogenic risks.…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer

Pan

Zhang

et al. 2021

Front. Pharmacol.

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The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX–induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients.

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“…Nrf2 and its downstream targets play a significant role in cardiovascular homeostasis caused by suppressing oxidative stress. They also regulate the onset and progression of heart failure [62]. Nrf2, in particular, controls the transcriptional activation of antioxidant genes by binding with ARE [62].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Protective Effect of Kirenol against Doxorubicin-Induced Cardiac Hypertrophy in H9c2 Cells through Nrf2 Signaling via PI3K/AKT Pathways

Alzahrani

Veeraraghavan

Hanieh

2021

IJMS

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Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis.

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Natural compounds against doxorubicin‐induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway

Cited by 81 publications

References 158 publications

RETRACTED: mtROS-mediated Akt/AMPK/mTOR pathway was involved in Copper-induced autophagy and it attenuates Copper-induced apoptosis in RAW264.7 mouse monocytes

RETRACTED: mtROS-mediated Akt/AMPK/mTOR pathway was involved in Copper-induced autophagy and it attenuates Copper-induced apoptosis in RAW264.7 mouse monocytes

Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer

Cardiac Protective Effect of Kirenol against Doxorubicin-Induced Cardiac Hypertrophy in H9c2 Cells through Nrf2 Signaling via PI3K/AKT Pathways

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