Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. Understanding the mechanisms by which doxorubicin leads to cardiomyocyte death may help identify novel therapeutic agents and lead to more targeted approaches to cardiotoxicity testing.

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Regulated cell death pathways in doxorubicin-induced cardiotoxicity

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Guidelines for the use and interpretatoin of assays for monitoring autophagy

Unraveling the mystery of cell death is one of the most fundamental progresses of life sciences during the past decades. Regulated cell death (RCD) or programmed cell death (PCD) is not only essential in embryonic development, but also plays an important role in the occurrence and progression of diseases, especially cancers. Escaping of cell death is one of hallmarks of cancer. Pyroptosis is an inflammatory cell death usually caused by microbial infection, accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). Gasdermin family proteins are the executors of pyroptosis. Cytotoxic N-terminal of gasdermins generated from caspases or granzymes proteases mediated cleavage of gasdermin proteins oligomerizes and forms pore across cell membrane, leading to release of IL-1β, IL-18. Pyroptosis exerts tumor suppression function and evokes anti-tumor immune responses. Therapeutic regimens, including chemotherapy, radiotherapy, targeted therapy and immune therapy, induce pyroptosis in cancer, which potentiate local and systemic anti-tumor immunity. On the other hand, pyroptosis of normal cells attributes to side effects of anti-cancer therapies. In this review, we focus on the regulatory mechanisms of pyroptosis and the tumor suppressive function of pyroptosis. We discuss the attribution of pyroptosis in reprogramming tumor microenvironments and restoration of anti-tumor immunity and its potential application in cancer immune therapy.

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Pyroptosis: a new paradigm of cell death for fighting against cancer.

Bioactive chemical constitutes from the root of Salvia miltiorrhiza classified in two major groups, viz., liposoluble tanshinones and water-soluble phenolics. Tanshinone IIA is a major lipid-soluble compound having promising health benefits. The in vivo and in vitro studies showed that the tanshinone IIA and salvianolate have a wide range of cardiovascular and other pharmacological effects, including antioxidative, anti-inflammatory, endothelial protective, myocardial protective, anticoagulation, vasodilation, and anti-atherosclerosis, as well as significantly help to reduce proliferation and migration of vascular smooth muscle cells. In addition, some of the clinical studies reported that the S. miltiorrhiza preparations in combination with Western medicine were more effective for treatment of various cardiovascular diseases including angina pectoris, myocardial infarction, hypertension, hyperlipidemia, and pulmonary heart diseases. In this review, we demonstrated the potential applications of S. miltiorrhiza, including pharmacological effects of salvianolate, tanshinone IIA, and its water-soluble derivative, like sodium tanshinone IIA sulfonate. Moreover, we also provided details about the clinical applications of S. miltiorrhiza preparations in controlling the cardiovascular diseases.

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Salvia miltiorrhiza in Treating Cardiovascular Diseases: A Review on Its Pharmacological and Clinical Applications.

The consumption of plant-based food is important for health promotion, especially concerning the prevention and management of chronic diseases. Flavonoids are the main bioactive compounds in citrus fruits, with multiple beneficial effects, especially antidiabetic effects. We systematically review the potential antidiabetic action and molecular mechanisms of citrus flavonoids based on in vitro and in vivo studies. A search of the PubMed, EMBASE, Scopus, and Web of Science Core Collection databases for articles published since 2010 was carried out using the keywords citrus, flavonoid, and diabetes. All articles identified were analyzed, and data were extracted using a standardized form. The search identified 38 articles, which reported that 19 citrus flavonoids, including 8-prenylnaringenin, cosmosiin, didymin, diosmin, hesperetin, hesperidin, isosiennsetin, naringenin, naringin, neohesperidin, nobiletin, poncirin, quercetin, rhoifolin, rutin, sineesytin, sudachitin, tangeretin, and xanthohumol, have antidiabetic potential. These flavonoids regulated biomarkers of glycemic control, lipid profiles, renal function, hepatic enzymes, and antioxidant enzymes, and modulated signaling pathways related to glucose uptake and insulin sensitivity that are involved in the pathogenesis of diabetes and its related complications. Citrus flavonoids, therefore, are promising antidiabetic candidates, while their antidiabetic effects remain to be verified in forthcoming human studies.

Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies.

It has been observed that many phytochemicals, frequently present in foods or beverages, show potent chemopreventive or therapeutic properties that selectively affect cancer cells. Numerous studies have demonstrated the anticancer activity of xanthohumol (Xn), a prenylated flavonoid isolated from hops (Humulus lupulus L.), with a concentration up to 0.96 mg/L in beer. This review aims to summarize the existing studies focusing on the anticancer activity of Xn and its effects on key signaling molecules. Furthermore, the limitations of current studies and challenges for the clinical use of Xn are discussed.

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Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.).

Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.

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Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.

Background Huai Hua San (HHS), a famous Traditional Chinese Medicine (TCM) formula, has been widely applied in treating ulcerative colitis (UC). However, the interaction of bioactives from HHS with the targets involved in UC has not been elucidated yet. Aim A network pharmacology-based approach combined with molecular docking and in vitro validation was performed to determine the bioactives, key targets, and potential pharmacological mechanism of HHS against UC. Materials and methods Bioactives and potential targets of HHS, as well as UC-related targets, were retrieved from public databases. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis, including protein-protein interaction (PPI), as well as the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, molecular docking was carried out to predict the combination of active compounds with core targets. Lastly, in vitro experiments were conducted to further verify the findings. Results A total of 28 bioactive ingredients of HHS and 421 HHS-UC-related targets were screened. Bioinformatics analysis revealed that quercetin, luteolin, and nobiletin may be potential candidate agents. JUN, TP53, and ESR1 could become potential therapeutic targets. PI3K-AKT signaling pathway might play an important role in HHS against UC. Moreover, molecular docking suggested that quercetin, luteolin, and nobiletin combined well with JUN, TP53, and ESR1, respectively. Cell experiments showed that the most important ingredient of HHS, quercetin, could inhibit the levels of inflammatory factors and phosphorylated c-Jun, as well as PI3K-Akt signaling pathway in LPS-induced RAW264.7 cells, which further confirmed the prediction by network pharmacology strategy and molecular docking. Conclusion Our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HHS against UC. It also provided a promising strategy to uncover the scientific basis and therapeutic mechanism of TCM formulae in treating diseases.

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Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Huai Hua San Against Ulcerative Colitis.

Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX-induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3-10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX-injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone) 1, and glutamate-cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA-induced Nrf2 activation and reversed the effect of Tan IIA on the DOX-induced inhibition of cell viability. These results suggest that the Nrf2-dependent antioxidant response mediates the protective effect of Tan IIA on DOX-induced cardiotoxicity.

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Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

Doxorubicin (Dox) is widely used in cancer therapy, but the clinical application is limited by its cardiotoxicity The underlying mechanism of Dox-induced cardiotoxicity remains unclear Present study aimed to evaluate the role of NLRP3 inflammasome in Dox-induced cardiotoxicity The NLRP3 inflammasome was activated in the myocardium of Dox-treating (5 mg/kg, once every other day, cumulative dosage to 15 mg/kg and sacrificed after 2 days of last Dox injection) C57BL/6 mice as shown by the up-regulation of NLRP3 and Caspase-1 p20 Dox (1 μM for 48 h) induced the apoptosis of H9c2 cells and primary cardiomyocytes concomitantly with up-regulation of NLRP3, ASC and Caspase-1 p20 expressions, as well as the increased IL-1β secretion, suggesting the activation of NLRP3 inflammasome These effects of Dox on H9c2 cells and primary cardiomyocytes can be reversed by MCC950, a specific inhibitor of NLRP3 In view of the key role of ROS on the Dox-induced cardiotoxicity, the relationship between ROS and NLRP3 was further investigated The ROS level was increased in myocardium, H9c2 cells and primary cardiomyocytes after treating with Dox Decreasing ROS level by NAC can inhibit the NLRP3 inflammasome activation, secretion of IL-1β and apoptosis in Dox-treating H9c2 cells and primary cardiomyocytes Collectively, this study reveals a crucial role of ROS/NLRP3-associated inflammasome activation in Dox-induced cardiotoxicity, and NLRP3 inflammasome may represent a new therapeutic target for Dox-induced cardiotoxicity

Shanshan Wei

Papers

Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.).

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.

Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Huai Hua San Against Ulcerative Colitis.

Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity.