Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats

Zare, Masoud; Rakhshan, Kamran; Aboutaleb, Nahid; Nikbakht, Farnaz; Naderi, Nasim; Bakhshesh, Morteza; Azizi, Yaser

doi:10.1016/j.lfs.2019.116623

Cited by 87 publications

(61 citation statements)

References 28 publications

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“…Nevertheless, the CYP1B1 selective inhibitor TMS has been shown to protect from chronic DOX-induced cardiotoxicity in male Sprague-Dawley rats in vivo and in RL-1 cardiomyocyte-like cells in vitro [74]. As summarized in Table 3, the cardioprotective effects of CYP1B1 inhibitors have been shown to be mediated by reduction in oxidative stress and apoptosis [185][186][187][188], improving mitochondrial function [189], reversing altered energy metabolism [190], protection from DOX-induced senescence in vascular smooth muscle cells [191], and reducing mid-chain HETEs concentration [74].…”

Section: Cardioprotective Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

“…Inhibition of CYP1B1 may interplay with these pathways leading to the chemo-sensitizing effects. [194] Isorhamnetin 17 [219] Protection from chronic DOX-induced cardiotoxicity in vivo in rats and in vitro in H9c2 cells [201] Potentiates DOX-induced toxicity in MCF-7, HepG2, and Hep2 cancer cells [201] Chrysin 24-270 [219,220] Protection from acute and chronic DOX-induced cardiotoxicity in vivo in rats [222,223] Enhanced cytotoxicity of DOX in a spheroid culture model of human lung squamous cell carcinoma [224], BEL-7402/ADM [225], lung cancer A549 cells [192], and human non-small-cell lung cancer cell lines [193] Apigenin 25 [219] Attenuated chronic DOX-induced cardiotoxicity in in vivo in rats and in vitro in rat cardiomyocytes [186][187][188] Augmented the cytotoxic effect of DOX against HepG2 cells [203], and DOX-resistant hepatocellular carcinoma cell line BEL-7402/ADM [204,218,226] Reverse chemo-resistance to DOX in DOX-resistant breast cancer cells (MCF-7/ADR) [198] Kaempferol 47 [219] Protected from chronic DOX-induced cardiotoxicity in vivo in rats and in vitro in H9c2 cells [227] Potentiated the cytotoxic effect of DOX in glioblastoma cells [205] Quercetin 77 [219] Protected rat and human cardiomyocytes and H9c2 cells from DOX-induced toxicity in vitro [176,188,189,199,228]. Protected from chronic DOX in rats [190,229] and mice [185] in vivo.…”

Section: Chemosensitizing Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

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CYP1B1 as a therapeutic target in cardio-oncology

2020

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Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

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Section: Cardioprotective Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

Section: Chemosensitizing Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

CYP1B1 as a therapeutic target in cardio-oncology

2020

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“…Thus, they also have the ability to alleviate side effects of chemotherapy. However, the antioxidant effect of these substances might be, at the same time, unfavorable in treatment because they can weaken the effectiveness of drugs that act by generating free radicals [ 46 ]. It is difficult to predict the exact path of flavonoid activity.…”

Section: Discussionmentioning

confidence: 99%

Apigenin and Hesperidin Downregulate DNA Repair Genes in MCF-7 Breast Cancer Cells and Augment Doxorubicin Toxicity

et al. 2020

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A number of studies have confirmed anti-tumor activity of flavonoids and their ability to enhance the effectiveness of classical anticancer drugs. The mechanism of this phenomenon is difficult to explain because of the ambivalent nature of these compounds. Many therapeutic properties of these compounds are attributed to their antioxidant activity; however, it is known that they can act as oxidants. The aim of this study was to assess the influence of apigenin and hesperidin on MCF-7 breast cancer cells with doxorubicin. The cytotoxic effect was determined using an MTT test and cell cycle analysis. To evaluate the possible interaction mechanism, reduced glutathione levels, as well as the DNA oxidative damage and the double strand breaks, were evaluated. Additionally, mRNA expression of genes related to DNA repair was assessed. It was demonstrated that flavonoids intensified the cytotoxic effect of doxorubicin despite flavonoids reduced oxidative damage caused by the drug. At the same time, the number of double strand breaks significantly increased and expression of tested genes was downregulated. In conclusion, both apigenin and hesperidin enhance the cytotoxic effects of doxorubicin on breast cancer cells, and this phenomenon occurs regardless of oxidative stress but is accompanied by disorders of DNA damage response mechanisms.

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“…CK-MB generally is present in cellular partitions and releases into circulation due to myocardial damage. [28] Troponins I is a myocardial tissue like protein, which is implicated in myocardial cell damage. Thus, cardiac troponins are favored indicators for identification of myocardial F I G U R E 4 Effect of serum AST, CK, and LDH levels in control and experimental rats.…”

Section: Discussionmentioning

confidence: 99%

Nimbolide prevents myocardial damage by regulating cardiac biomarkers, antioxidant level, and apoptosis signaling against doxorubicin‐induced cardiotoxicity in rats

Xia

Chen

et al. 2020

J Biochem & Molecular Tox

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The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)‐treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, whereas reduced body weight, heart weight, blood pressure indices and reduced levels of antioxidants like glutathione‐S‐transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase were observed in the heart tissue of DOX‐treated animals. DOX‐treated animals showed augmented levels of cardiac markers likes monocyte chemotactic protein‐1, interferon‐gamma, aspartate transferase, creatine kinase, lactate dehydrogenase, creatine kinase‐muscle/brain, heart‐type fatty acid‐binding protein, glycogen phosphorylase isoenzyme BB, transforming growth factor‐β, brain natriuretic peptide, myoglobin, and cTnI in serum. Histopathological assessment confirmed the DOX‐induced cardiotoxicity. Furthermore, DOX‐induced rats showed augmented inflammatory mediators (nuclear factor‐κB [NF‐kB], tumor necrosis factor‐α [TNF‐α], and interleukin‐1β [IL‐1β]) and increased PI3K/Akt signaling proteins (PI3K, p‐Bad/Bad, caspase‐3, and p‐Akt), whereas decreased oxidative markers (HO‐1 and NQO‐1) and p‐PTEN were observed. Nimbolide‐supplemented rats showed reduced activity/levels of cardiac markers and TBARS levels in serum and heart tissue. Levels of enzymatic and nonenzymatic antioxidants were augmented in the heart tissue of nimbolide‐supplemented rats. Nimbolide influence decreased apoptosis, inflammation, and enhanced antioxidant markers through the modulation of p‐Bad/Bad, caspase‐3, PI3K, p‐Akt, TNF‐α, NF‐kB, IL‐1β, HO‐1, NQO‐1, and p‐PTEN markers. The histopathological explanations were observed to be in line with biochemical analysis. Therefore, the finding of current work was that nimbolide has a defensive effect on the myocardium against DOX‐induced cardiac tissue damage.

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Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats

Cited by 87 publications

References 28 publications

CYP1B1 as a therapeutic target in cardio-oncology

CYP1B1 as a therapeutic target in cardio-oncology

Apigenin and Hesperidin Downregulate DNA Repair Genes in MCF-7 Breast Cancer Cells and Augment Doxorubicin Toxicity

Nimbolide prevents myocardial damage by regulating cardiac biomarkers, antioxidant level, and apoptosis signaling against doxorubicin‐induced cardiotoxicity in rats

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