Introduction

Doxorubicin (Adriamycin), an antibiotic derived from the Streptomyces peucetius, is part of the anthracycline group of chemotherapeutic agents, which also includes daunorubicin, idarubicin, and epirubicin (Botta 2019; Zhang et al. 2020). Doxorubicin is used to treat soft tissue and bone sarcomas and cancers of the breast, ovary, bladder, and thyroid, acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, and small cell lung cancer (Dempke et al. 2023). The US FDA has approved a doxorubicin liposomal formulation for ovarian cancer in patients where platinum-based chemotherapy failed and in AIDS-related Kaposi sarcoma and multiple myeloma patients (Tantari et al. 2019). The recommended dose of doxorubicin to treat a variety of malignancies is 60 to 75 mg/m2/day intravenously every 21 days (Satyam et al. 2023). Doxorubicin is referred to as “red devil” chemotherapy due to its red color and potentially unpleasant side effects, particularly its irreversible cardiotoxicity (Dempke et al. 2023). Cumulative doses of doxorubicin over 550 mg/m2 increase significantly the risk of cardiomyopathy (Dempke et al. 2023). Clinically, doxorubicin-induced cardiotoxicity (DIC) is characterized by arrhythmias and heart failure (Yarmohammadi et al. 2021d). The mechanisms suggested responsible for DIC include oxidative stress, apoptosis, autophagy, and endoplasmic reticulum stress (Yarmohammadi et al. 2021d; Kong et al. 2022; Zhang et al. 2023).

Bibliographic analysis is a technique for understanding research trends in a particular field and provides a macro overview of large volumes of scientific data (Guerrero-Bote et al. 2021). Web of Science (WoS) and Scopus are the primary sources of bibliographic information (Pranckutė 2021). Bibliographic records are generally retrieved from bibliographic indexes by author name, keyword, and publication title (Donthu et al. 2021). Keywords are the terms selected by authors that summarize and present the research content (Lu et al. 2020). The bibliographic analysis of author-defined keywords helps to better understand the structure of research trends (Lu et al. 2020).

During the last decades, researchers have selected various keywords for research papers based on the identified mechanisms involved in DIC (Xiao et al. 2019; Yarmohammadi et al. 2021e, d). This study uses author-keyword analysis to characterize the molecular mechanisms involved in DIC research literature over the years. Since no bibliometrics studies have appeared in this field, we performed a bibliometrics analysis using the WoS database on the author keywords used in DIC studies.

Methodology

Search strategy

The WoS database provides the highest reliability and quality in terms of coverage of the DIC literature (Pranckutė 2021). The Web of Science Core Collection was searched to extract the research papers from inception to July 19, 2023. A syntax search was designed using doxorubicin and cardiotoxicity. The detailed search strategy is presented in Table 1. All document types were included. The search was refined by English language and eliminating retracted publications. Figure 1 shows the bibliometrics study flowchart.

Table 1 Search strategy
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Fig. 1
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Flowchart of the searching stagey in the bibliometrics study

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Bibliometrics and visualization analysis

The total number of publications retrieved for further analysis was 14,476. Data in the WoS database were downloaded under text format and imported into VOSviewer version 1.6.19 for further analysis. Nodes in the visualization network map show the journals and author keywords. The size of the nodes indicates the frequency of occurrence, and the color of the nodes reveals cluster membership for the journals and keywords. The bar and line graphs were generated using GraphPad Prism 8 (San Diego, CA, USA) and the matplotlib of Python 3.10.2, respectively.

Results

Distribution of documents by publication years

Figure 2 illustrates the number of DIC papers in WoS by publication year. The annual number of documents increased, reaching 14,476 articles on July 19, 2023. The first publication year was 1970, when only one paper was published by Mhatre et al. It was a meeting abstract entitled "Possible role of metabolites in cardiac toxicity induced by daunomycin (NSC-82,151) and adriamycin (NSC-123,127)" (Mhatre et al. 1970). The first article in the field of DIC was authored by Herman et al. in 1971. "Comparison of cardiovascular actions of daunomycin, adriamycin, and n-acetyl-daunomycin in hamsters and monkeys" was published in Pharmacology (publisher: KARGER) (Herman et al. 1971). The first review article reviewed the literature about DIC in a child with Wilms tumor and was published by Gerber et al. in the Journal of Pediatrics in 1975 (Gerber et al. 1975).

Fig. 2
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Annual number of publications from 1970 to 2023

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Journal bibliometrics analysis

A total of 2,187 sources published research related to DIC from 1970 to July 19, 2023. Figures 3a and 4a display the network of journals by documents and citations, respectively. The results from bibliometrics analysis using VOSviewer showed that the Journal of Clinical Oncology published 326 papers with 36,472 citations and had the highest citations and documents of any journal. Circulation ranks second in terms of number of documents, followed by Cancer Chemotherapy and Pharmacology, FASEB Journal, Journal of Molecular and Cellular Cardiology, Annals of Oncology, Cancer Research, Plos One, European Heart Journal, and Free Radical Biology and Medicine. The second rank in terms of the number of citations belongs to the New England Journal of Medicine, followed by Cancer, Annals of Oncology, Circulation, Cancer Research, Journal of the American College of Cardiology, Journal of Molecular and Cellular Cardiology, Biochemical Pharmacology, and Journal of Biological Chemistry. The top 10 most productive journals by documents or citation are listed in Figs. 3b and 4b, respectively.

Fig. 3
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(A) The network of journals by documents. Nodes, the size of nodes, and the color of nodes in the map show the journals, the frequency of occurrence of documents, and cluster membership for the journal, respectively. (B) The top 10 most productive journals by document

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Fig. 4
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(A) The network of journals by citations. Nodes, the size of nodes, and the color of nodes in the map show the journals, the frequency of occurrence of citations, and cluster membership for the journal, respectively. (B) The top 10 most productive journals by citations

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Document bibliometrics analysis

The results of this study revealed that the article published in Pharmacological Review by Minotti et al. “Anthracyclines: Molecular advances and pharmacological developments in anti-tumor activity and cardiotoxicity," had the most citation (2,749) among all documents (Minotti et al. 2004). The top 10 most productive documents by citation are listed in Table 2.

Table 2 The top 10 most productive documents by citations
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Author keywords bibliometric analysis

Author keywords were not available for older articles (the 1970s and 1980s); therefore, the bibliometrics keyword analysis started in the 1990s. Figure 5 reveals the co-occurrence author-keywords network. The top 50 author-keywords trend from 1990 to 2023 is listed in Table 3. The findings show that “doxorubicin” and “cardiotoxicity” are highly used keywords by authors from 1990 to 2023. The trend of using the keyword "adriamycin" has decreased, from rank 3 in 1990 to rank 22 in 2023. This reduction indicates that the tendency of authors to use the keyword "adriamycin" has declined over the years. The use of the keyword "heart failure" increased between 1990 (rank 16) and 2023 (rank 7). The keyword "oxidative stress" has grown with the recognition of oxidative stress as a primary cause of DIC. This keyword was one of the top 10 keywords in 2000–2023 and has become the third most popular keyword in recent years. The rank of “mitochondria” was 27 in the 1990s, 15 in the 2000s, 15 in the 2010s, and 14 from 2020 to July 19, 2023. The term “apoptosis” was ranked 46th in the 1990s. The frequency of usage of the keyword "apoptosis" has increased over the last three decades with the determination of its significance in inducing DIC. Apoptosis was one of the four keywords most used by the authors. The term "inflammation" (rank 124) and “autophagy” (rank 241) have been included in the author's keywords since the 2000s. Appearance time of keywords "mitophagy" (rank 244), "endoplasmic reticulum stress" (127), and "pyroptosis" (rank 490) was the 2010s, and for “ferroptosis” (rank 17), it was from 2020 to July 19, 2023. In general, the evolution of the research process in the field of involved mechanisms in DIC was as follows oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis (Fig. 6, a). The “glutathione,” “glutathione peroxidase,” “superoxide dismutase,” and “caspase” were the most common author keywords in the 1990s, while their use decreased in the following decades. The most used terms in the 2000s and 2010s were “reactive oxygen species” and “p53”. The “Nrf2”, “TNF-alpha,” and “nuclear factor-kappa beta” in the field of DIC were employed for the first time in the 2010s. “NLRP3” was used for the first time from 2020 to July 19, 2023 (Fig. 6b, c, and d). The different types of intracellular signaling pathways regulators are found in the field of DIC research. Regulators-related author keywords are listed in Fig. 7. The highest frequency of occurrence was reported for “AKT,” “Sirt1,” and “AMPK,” respectively.

Fig. 5
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The co-occurrence author keywords network. Nodes, the size of nodes, and the color of nodes in the map show the author keywords, the frequency of occurrence of the author keywords, and cluster membership for the author keywords, respectively

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Table 3 The top 50 author keywords from 1990 to July 19, 2023
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Fig. 6
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The most common author keywords in the field of mechanisms involved in DIC. The main mechanism of cardiotoxicity-related author keywords trends from 1990–2023 (a), the main oxidative stress-related author keywords (b), the main apoptosis-related author keywords (c), and the main inflammation-related author keywords (d)

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Fig. 7
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Regulators of signaling pathways-related author keywords from 1990 to July 19, 2023

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Discussion

The current study showed that the annual number of DIC-related publications in WoS increased and reached 14,476 documents on July 19, 2023. The Journal of Clinical Oncology is the leading journal in this field, with the highest number of citations (36,472 citations) and documents (326 publications). The top-cited paper (with 2,749 citations) was published in the Pharmacological Review by Minotti et al. in 2004. The top five keywords with high frequency were "doxorubicin," "cardiotoxicity," "adriamycin," “chemotherapy,” and “anthracyclines.” According to the results of this study, the most common mechanisms involved in DIC were oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis. The highest occurrences of regulators-related author keywords were reported for "AKT," "Sirt1," and "AMPK," respectively. Based on the results of VOSviewer, we reviewed the hot research molecular mechanisms and signaling pathways involved in DIC.

Molecular mechanisms involved in DIC

Oxidative stress

Oxidative stress is one of the main mechanisms of doxorubicin cardiotoxicity (Yarmohammadi et al. 2021e). Overproduction and massive accumulation of reactive species in cardiomyocytes during doxorubicin treatment induce oxidative stress (Yarmohammadi et al. 2021e). Increased free radical levels in cardiac cells are associated with mitochondrial dysfunction, calcium homeostasis dysregulation, and protein synthesis attenuation (Shinlapawittayatorn et al. 2022). During oxidative stress, the transcription factor, the nuclear factor erythroid 2-related factor 2 (Nrf2), regulates the expression of antioxidant genes such as glutathione, glutathione peroxidase, superoxide dismutase, and hemoxygenase-1 (Yarmohammadi et al. 2021e). Evidence demonstrated a significant reduction of cardiac antioxidant levels in hearts treated by doxorubicin (Singh et al. 2023). Overexpression of antioxidant proteins enhanced ROS elimination and reduced DIC (Yarmohammadi et al. 2021e; Singh et al. 2023).

Apoptosis

The apoptosis process is recognized as programmed cell death (D’arcy 2019). Apoptosis of myocardiocytes plays a critical role in the development of DIC (Singh et al. 2023). The B-cell lymphoma 2 (Bcl-2) family members, such as the antiapoptotic marker Bcl-2 and the pro-apoptotic marker, the Bcl-2-associated X protein (Bax), regulate the permeabilization of the mitochondrial outer membrane (Hope et al. 2019). The promotion of pro-apoptotic signals by doxorubicin-mediated oxidative stress triggers the inhibition of Bcl-2 and the activation of Bax, leading to the release of cytochrome c and subsequently the induction of caspase and cardiac apoptosis (Heimer et al. 2019; Hope et al. 2019).

Inflammation

Inflammation is one of the hallmark mechanisms implicated in the evolution of DIC (Yarmohammadi et al. 2021c). A remarkable increase in myocardium levels of the nuclear factor-kappa B (NF-κB) has been reported following doxorubicin treatment (Yarmohammadi et al. 2021c). The transcription factor NF-κB triggers the synthesis of inflammatory cytokines, such as the tumor necrosis factor-alpha (TNF-α) (Yu et al. 2020). These cytokines recruit the infiltration of leukocytes into the cardiomyocytes to further exacerbate the doxorubicin-induced cardiac inflammatory responses (Yu et al. 2020).

Autophagy and mitophagy

Autophagy is one of the main cellular degradation processes for maintaining cellular homeostasis under physiological conditions (Aman et al. 2021). Damaged cytoplasmic components are degraded by autophagosomes, the central organelle in autophagy, and subsequently, lysosomes (Aman et al. 2021). The removal of impaired mitochondria by autophagy is known as the mitophagy process (Onishi et al. 2021). Dysregulated autophagy and mitophagy genes expression, such as Beclin1 and the microtubule-associated protein 1A/1B-light chain 3 (LC3) and the PTEN-induced kinase 1 (PINK1), in cardiomyocytes by doxorubicin treatment have been demonstrated (Xiao et al. 2019; Wu et al. 2023). Therefore, autophagy and mitophagy contribute to the pathogenesis of cardiomyopathy in doxorubicin treatment (Xiao et al. 2019; Wu et al. 2023).

Endoplasmic reticulum stress

Cells respond to the accumulation of misfolded and unfolded proteins by activating the unfolded protein response (UPR) in the endoplasmic reticulum (ER) that resolves the accumulation of proteins (Yarmohammadi et al. 2021d). Under severe or prolonged stress, the ER stress signaling switches from pro-survival to pro-death (Lemmer et al. 2021). Various sensors, such as the activating transcription factor 6 (ATF6), the protein kinase-like ER kinase (PERK), and the inositol-requiring kinase 1α (IRE1α), are involved in ER stress (Ren et al. 2021). Induction of ER stress is reported to be a key contributor to doxorubicin cardiac complication (Yarmohammadi et al. 2021d).

Pyroptosis

Pyroptosis is caspase-1-induced inflammatory cell death (Wang et al. 2020a). The NLR family pyrin domain containing 3 (NLRP3) is a primary sensor of cellular stress that triggers caspase-1 activation (Wang et al. 2020a). Activated caspase-1 is responsible for the induction of plasma membrane pores and the release of pro-inflammatory mediators, including interleukins (Molla et al. 2020). Recent studies have shown that doxorubicin elevated cardiac pyroptosis by upregulating markers such as NLRP3, caspase-1, and interleukin-18 (Zhang et al. 2021b).

Ferroptosis

Ferroptosis is an iron accumulation and lipid peroxidation-dependent form of cell death (Yarmohammadi et al. 2021a). The inactivation of glutathione peroxidase 4 (GPx4) has been recognized as an essential ferroptosis regulator (Ursini and Maiorino 2020). GPx4 controls ferroptosis by detoxifying toxic lipid peroxides and glutathione oxidation (Ursini and Maiorino 2020). Down-regulation of GPx4 and subsequent induction of lipid peroxidation by doxorubicin have been suggested to lead to cardiac ferroptosis (Wang et al. 2022).

Signaling pathways involved in DIC

During doxorubicin treatment, the overproduction of ROS leads to an increase in the AMP/ATP ratio and its subsequent activation of the AMP-activated protein kinase (AMPK), a primary sensor of cellular energy (Tabrizi et al. 2022). The mitogen-activated protein kinases (MAPKs) belong to the family of serine/threonine protein kinases that regulate numerous cellular processes, including stress response and apoptosis (Yue and López 2020). This family consists of the c-Jun N-terminal kinase (JNK), p38 MAPK, and the extracellular-signal-regulated kinase 1 and 2 (ERK1/2) pathways (Yue and López 2020). AMPK causes cardiac apoptosis by activating the MAPK pathways (Chen et al. 2020). AMPK is also known as an activator of the tuberous sclerosis complex 2 (TSC2), a negative regulator of the mammalian target of rapamycin (mTOR) (Zhang et al. 2021a). The mTOR, a protein kinase, functions as an essential controller of cardiac metabolism in response to raised AMP/ATP ratio (He et al. 2022).

Phosphoinositide 3‐kinase (PI3K) phosphorylates the phosphatidylinositol‐4,5‐bisphosphate (PIP2), a membrane phospholipid, to generate the phosphatidylinositol‐3,4,5‐trisphosphate (PIP3) (Yarmohammadi et al. 2021b). PIP3 recruits the protein kinases AKT to the cell membrane and contributes to its phosphorylation and activation by the phosphoinositide-dependent kinase-1 (PDK1) (Levina et al. 2022). Activated AKT modulates cardiac apoptosis and autophagy pathways by activating several downstream pathways (Ghafouri-Fard et al. 2022). Moreover, AKT can induce mTOR activity by the inhibition of TSC2 (Gao et al. 2020). Sirtuins (SIRTs) are the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases proteins with seven members (SIRT1–7) (Tabrizi et al. 2022). These proteins regulate critical physiological pathways, including AMPK, mTOR, and PI3K/AKT signaling pathways (Wang et al. 2020b). The forkhead box O3 (FoxO3a), a central transcription factor, has been suggested as a homeostasis regulator (Fasano et al. 2019). AMPK is known as an upstream positive regulator of FoxO3a (Fasano et al. 2019). The AMPK/FOXO3a signaling pathway promotes myocardial autophagy by up-regulating autophagy-related genes (Liang et al. 2021). The signal transducer and activator of transcription 3 (STAT3) is another critical transcription factor that has a key role in multiple cellular processes, such as inflammation and apoptosis (Harhous et al. 2019). The AMPK signaling pathway negatively regulates STAT3 activity (Gong et al. 2020). Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), a transcription coactivator, plays a major role in cardiac energy metabolism regulation (Chen 2023). PGC-1α-dependent transcription is enhanced by different sensors, such as AMPK and SIRT1, under doxorubicin-induced energy depletion (Chen 2023).

Conclusion

This study analyzed author-defined keywords from more than 14,000 documents related to DIC. Based on the results, oxidative stress, apoptosis, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, pyroptosis, and ferroptosis were hot research mechanisms of DIC during the last 50 years. Moreover, much of the research focused on mechanisms around "AKT," "Sirt1," and "AMPK" regulators. Future studies should focus on research related to the signaling mechanisms with an aim toward developing therapeutics for the cardioprotective effects of natural compounds against DIC.