Doxorubicin-induced Cardiotoxicity and Cardioprotective Agents: Classic and New Players in the Game

Arruda, Felipe dos Santos; Tomé, Fernanda Dias; Miguel, Marina Pacheco; Menezes, Liliana Borges de; Nagib, Patrícia Resende Alo; Campos, Erica C.; Soave, Danilo Figueiredo; Celes, Mara Rúbia Nunes

doi:10.2174/1381612825666190312110836

Cited by 18 publications

(9 citation statements)

References 73 publications

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“…The exact mechanism by which anthracyclines induce cardiotoxicity remains unclear. The molecular mechanisms of anthracyclines involve multiple aspects, including lipid peroxidation, accumulation of reactive oxygen species, DNA damage, and mitochondrial dysfunction (8). Autophagy dysfunction plays…”

Section: Discussionmentioning

confidence: 99%

Qishen Huanwu capsule reduces pirarubicin-induced cardiotoxicity in rats by activating the PI3K/Akt/mTOR pathway

Wang

Jiao

et al. 2020

Ann Palliat Med

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Background: One of the common adverse reactions to anthracyclines, a group of chemotherapeutics, is cardiotoxicity. Cancer patients receiving anthracycline-based chemotherapeutic regimens often discontinue treatment due to cardiotoxicity. How to prevent and reduce the cardiotoxicity of anthracyclines is one of the hot topics in the field of onco-cardiology. Traditional Chinese medicine can reduce the toxic side effects of chemotherapeutics. The present study aimed to investigate the protective effect of Qishen Huanwu capsule (QSHWC) on pirarubicin (THP)-induced myocardial injury in rats and the underlying mechanisms.Methods: Forty-eight male Sprague-Dawley (SD) rats were randomly divided into six groups: control group, THP, low-dose QSHWC, moderate-dose QSHWC, high-dose QSHWC, and LY294002[phosphatidylinositol 3-kinase (PI3K) inhibitor] (n=8 each). Echocardiographic examination was performed to examine heart structure and function. Hematoxylin and eosin (HE) staining was conducted to examine histopathological changes in myocardial tissue. Immunofluorescence staining was carried out to examine the expression of the autophagosome-specific marker protein microtubule-associated protein 1 light chain 3 (LC3). Western blot was performed to analyze the expression of LC3-I, LC3-II, PI3K, phosphorylated (p)-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR), and p-mTOR.Results: Compared with the control group, the THP group had a higher left ventricular end-systolic diameter (LVESD), lower left ventricular ejection fraction (LVEF), lower left ventricular fractional shortening (LVFS), and inferior heart function. In addition, compared with the control group, the THP group had significantly higher LC3 protein expression, a significantly higher LC3-II/LC3-I ratio (P<0.05), and significantly lower p-PI3K, p-Akt, and p-mTOR (P<0.05). QSHWC attenuated the THP-induced decline in heart function, downregulated LC3 protein in rat myocardial tissue, decreased the LC3-II/LC3-I ratio, and increased p-PI3K, p-Akt, and p-mTOR. In the LY294002 group, the above effects of QSHWC were reversed.Conclusions: QSHWC alleviated THP-induced myocardial injury. The underlying mechanism was related to the activation of the PI3K/Akt/mTOR pathway and the mitigation of the excessive autophagy of cardiomyocytes caused by THP.

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Section: Discussionmentioning

confidence: 99%

Qishen Huanwu capsule reduces pirarubicin-induced cardiotoxicity in rats by activating the PI3K/Akt/mTOR pathway

Wang

Jiao

et al. 2020

Ann Palliat Med

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“…BMSCs were counted using Kit-8 (CCK-8, Sigma, Barcelona, Spain) to assess proliferation at four different time periods (1,5,7, and 14 days) by seeding them at a density of 10 × 10 3 cells/well in 96-well plates, then each well was treated with CCK-8 reagent and put into a CO 2 incubator for three hours. Using a microplate spectrophotometer, we determined the optical density at 450 nm (Epoch, Biotek Instruments, Winooski, VT, USA).…”

Section: Assessment Of Cell Proliferation and Viabilitymentioning

confidence: 99%

“…High dosages and continuous usage of DOX may cause hepatotoxicity, adipose tissue damage, cardiotoxicity, and recurrent and resistant malignancies [6]. DOX-induced liver impairment varies from non-specific alterations in liver structure to acute liver failure, cirrhosis, jaundice, and an increase in serum liver enzyme AST as well as ALT [7].…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway

Awadalla

Hamam

Mostafa

et al. 2023

Cells

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Background: Doxorubicin (DOX) is widely used to treat a variety of malignancies in both adults and children, including those of the bladder, breast, stomach, and ovaries. Despite this, it has been reported to cause hepatotoxicity. The recent discovery of bone marrow-derived mesenchymal stem cells’ (BMSCs) therapeutic effects in the context of liver diseases suggests that their administration plays a part in the mitigation and rehabilitation of drug-induced toxicities. Objectives: This study investigated whether bone BMSCs could reduce DOX-induced liver damage by blocking the Wnt/β-catenin pathway that causes fibrotic liver. Materials and methods: BMSCs were isolated and treated with hyaluronic acid (HA) for 14 days before injection. Thirty-five mature male SD rats were categorized into four groups; group one (control) rats were supplemented with saline 0.9% for 28 days, group two (DOX) rats were injected with DOX (20 mg/kg), group three (DOX + BMSCs) rats were injected with 2 × 106 BMSCs after 4 days of DOX injection, group four (DOX + BMSCs + HA) rats were injected with 0.1 mL BMSCs pretreated with HA after 4 days of DOX. After 28 days the rats were sacrificed, and blood and liver tissue samples were subjected to biochemical and molecular analysis. Morphological and immunohistochemical observations were also carried out. Results: In terms of liver function and antioxidant findings, cells treated with HA showed considerable improvement compared to the DOX group (p < 0.05). Moreover, the expression of inflammatory markers (TGFβ1, iNos), apoptotic markers (Bax, Bcl2), cell tracking markers (SDF1α), fibrotic markers (β-catenin, Wnt7b, FN1, VEGF, and Col-1), and ROS markers (Nrf2, HO-1) was improved in BMSCs conditioned with HA in contrast to BMSCs alone (p < 0.05). Conclusion: Our findings proved that BMSCs treated with HA exert their paracrine therapeutic effects via their secretome, suggesting that cell-based regenerative therapies conditioned with HA may be a viable alternative to reduce hepatotoxicity.

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“…Lots of available studies on doxorubicin adverse effects are focused on its cardiotoxicity. However, the administration of DOX is also frequently associated with toxic injury to the liver, and may intensify the rate of transient increase in serum liver enzyme and acute liver injury with jaundice that can be severe and even life-threatening (6). The production of ROS is the major consequence of its redox cycling profile and is considered as a double-edged sword, which functions not only on cancer cells but also on several normal cells throughout the body.…”

Section: None Herbal Agents As Preventive and Therapeutic Measures Fo...mentioning

confidence: 99%

None Herbal Agents as Preventive and Therapeutic Measures for Doxorubicin Induced Hepatotoxicity: A Comprehensive Review

Mahmoudi¹,

Elyasi²

2022

jpc

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Cancer is one of the most common human diseases and a leading cause of human mortality in rencent years. Doxorubicin (DOX) is an important anti-cancer agent belonging to anthracyclines drug category. This chemotherapeutic agent acts against cancer cells through different mechanisms; however, its use is related with numerous acute and chronic dose-related side effects and toxicities including hepatotoxicity. The aim of this study was to conduct a comprehensive review of in vitro, in vivo and any human studies regarding the protective effects of synthetic compounds against DOX-induced liver injury.The search was conducted in embase, PubMed and Scopus databases using the following keywords: “doxorubicin”, “Adriamycin”, “hepatotoxicity”, “liver injury”, “liver damage” and “hepatoprotective” to find experimental and preclinical studies regarding the effects of various compounds on DOX-induced hepatotoxicity. Twenty-one eligible studies to the end of May 2022 finally were reviewed (19 in vivo and 2 both in vivo and in vitro studies). Our results demonstrated that all of these drugs, except acetylsalicylic acid, had considerable hepatoprotective effects against DOX (deferoxamine had a mild effect). In addition, except glutathione, none of the studied drugs and compounds attenuated the antitumor efficacy of DOX treatment. Moreover, no human study was available in this fieild. Altogether, our results demonstrated that most of compounds with anti-apoptosis, anti-inflammatory and antioxidant properties are efficacious against DOX-induced hepatotoxicity and may have potential for being considered for inclusion in the chemotherapeutic regimes of cancer patients, after fully been assessed in well-desgined large clinical trials.

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Doxorubicin-induced Cardiotoxicity and Cardioprotective Agents: Classic and New Players in the Game

Cited by 18 publications

References 73 publications

Qishen Huanwu capsule reduces pirarubicin-induced cardiotoxicity in rats by activating the PI3K/Akt/mTOR pathway

Qishen Huanwu capsule reduces pirarubicin-induced cardiotoxicity in rats by activating the PI3K/Akt/mTOR pathway

Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway

None Herbal Agents as Preventive and Therapeutic Measures for Doxorubicin Induced Hepatotoxicity: A Comprehensive Review

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