-
Heart Failure Reviews Jul 2021Chemotherapy with anthracycline-based regimens remains a cornerstone of treatment of many solid and blood tumors but is associated with a significant risk of... (Review)
Review
Chemotherapy with anthracycline-based regimens remains a cornerstone of treatment of many solid and blood tumors but is associated with a significant risk of cardiotoxicity, which can manifest as asymptomatic left ventricular dysfunction or overt heart failure. These effects are typically dose-dependent and cumulative and may require appropriate screening strategies and cardioprotective therapies in order to minimize changes to anticancer regimens or even their discontinuation. Our current understanding of cardiac damage by anthracyclines includes a central role of oxidative stress and inflammation. The identification of these processes through circulating biomarkers or imaging techniques might then be helpful for early diagnosis and risk stratification. Furthermore, therapeutic strategies relieving oxidative stress and inflammation hold promise to prevent heart failure development or at least to mitigate cardiac damage, although further evidence is needed on their efficacy, either alone or as part of combination therapies with neurohormonal antagonists, which are the current adopted standard.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Humans; Inflammation; Oxidative Stress
PubMed: 33319255
DOI: 10.1007/s10741-020-10063-9 -
Cancer therapeutics-related cardiovascular dysfunction: Basic mechanisms and clinical manifestation.Journal of Cardiology Mar 2023Although recent advances in cancer treatment improve cancer prognosis, cancer therapeutics-related cardiovascular dysfunction (CTRCD) significantly contributes to the... (Review)
Review
Although recent advances in cancer treatment improve cancer prognosis, cancer therapeutics-related cardiovascular dysfunction (CTRCD) significantly contributes to the global burden of cardiovascular disease. CTRCD causes two crucial issues: first, premature treatment interruption or discontinuation of chemotherapy; second, the development of congestive heart failure during and after cancer treatment. Thus, early detection and prompt treatment of CTRCD may improve the prognosis in cancer patients. This review covers representative anticancer drugs, including anthracyclines, human epidermal growth factor 2 inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. We focus on the molecular mechanisms of CTRCD and various approaches to diagnosis, prevention, monitoring, and treatment.
Topics: Humans; Cardiotoxicity; Early Detection of Cancer; Antineoplastic Agents; Antibiotics, Antineoplastic; Neoplasms
PubMed: 35589463
DOI: 10.1016/j.jjcc.2022.04.006 -
Molecules (Basel, Switzerland) Sep 2020Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed...
Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its toxicity, we used a Cathepsin B (Cat B)-sensitive prodrug concept for its targeted release since this enzyme is frequently overexpressed in cancer cells. Copper-free "click" chemistry was used to synthesize cPCPs containing up to four DOX moieties tethered to the upper face of the scaffold through a Cat B-cleavable peptidic linker (GAGRRAAG). On the lower part, PEG 5, 10 and 20 kDa and a fifth peptidyl DOX moiety were grafted in order to improve the solubility, bioavailability and pharmacokinetic profiles of the compound. In vitro results on HT1080 human fibrosarcoma cells showed that cPCPs display a delayed action that consists of a cell cycle arrest in the G2 phase comparable to DOX alone, and increased cell membrane permeability.
Topics: Amino Acid Sequence; Antibiotics, Antineoplastic; Cathepsin B; Cell Line, Tumor; Cell Membrane Permeability; Cell Survival; Click Chemistry; Doxorubicin; G2 Phase Cell Cycle Checkpoints; Humans; Peptides, Cyclic; Polyethylene Glycols; Prodrugs; Solubility
PubMed: 32962018
DOI: 10.3390/molecules25184285 -
Oxidative Medicine and Cellular... 2022Anthracyclines are chemotherapeutic agents widely used to treat a variety of cancers, and these drugs have revolutionized our management of cancer patients. The... (Review)
Review
Anthracyclines are chemotherapeutic agents widely used to treat a variety of cancers, and these drugs have revolutionized our management of cancer patients. The dose-dependent cardiotoxicity of anthracyclines, however, remains one of the leading causes of chemotherapy treatment-associated mortality in cancer survivors. Patient threshold doses leading to anthracycline-induced cardiotoxicity (AIC) are highly variable among affected patients. This variability is largely ascribed to genetic variants in individuals' genomes. Here, we briefly discuss the prevailing mechanisms underlying the pathogenesis of AIC, and then, we review the genetic variants, mostly identified through human genetic approaches and identified in cancer survivors. The identification of all genetic susceptibilities and elucidation of underlying mechanisms of AIC can help improve upfront risk prediction assessment for potentially severe cardiotoxicity disease and provide valuable insights into the understanding of AIC pathophysiology, which can be further leveraged to develop targeted pharmacogenetic therapies for those at high risk.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Cardiotoxicity; Genetic Predisposition to Disease; Humans; Neoplasms
PubMed: 35965684
DOI: 10.1155/2022/5818612 -
Biomedicine & Pharmacotherapy =... Feb 2023Doxorubicin (Dox)-induced cardiotoxicity has limited its use. Inflammation, oxidative stress, and apoptosis have important roles in Dox-induced cardiotoxicity....
BACKGROUND
Doxorubicin (Dox)-induced cardiotoxicity has limited its use. Inflammation, oxidative stress, and apoptosis have important roles in Dox-induced cardiotoxicity. Minocycline (Min) is an antibiotic with anti-inflammatory, anti-oxidant and anti-apoptotic properties. Here, the cardioprotective effects of Min against Dox-induced cardiotoxicity in adult male rats were evaluated.
METHODS
Forty-two adult male rats were divided into six groups including control group (normal saline), Dox group, Min groups (Min 45 mg/kg and Min 90 mg/kg), and treatment groups (Dox + Min 45 mg/kg and Dox + Min 90 mg/kg). Dox (2.5 mg/kg) was administered three times a week for two weeks, and Min once a day for three weeks via intraperitoneal route. Cardiac tissue sections were stained with hematoxylin and eosin for histological examination. The activities of lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) in serum as well as the activity of catalase and superoxide dismutase (SOD) in cardiac tissue were measured. Cardiac tissue levels of malondialdehyde (MDA), TNF-α, and IL-1β were also measured using ELISA.
RESULTS
Compared with the Dox group, treatment with Min significantly decreased the activity of LDH and CK-MB. Min also increased the activity of catalase and SOD in the tissue samples. The results showed that the levels of MDA, TNF-α, and IL-1β in cardiac tissue samples were significantly lower in the Min groups compared with the Dox group. In addition, histopathological results showed that Min reduced the tissue damage caused by Dox.
CONCLUSION
Min reduced Dox-induced cardiotoxicity. The anti-oxidant and anti-inflammatory properties of Min may contribute to its protective effects.
Topics: Rats; Male; Animals; Cardiotoxicity; Antioxidants; Catalase; Minocycline; Tumor Necrosis Factor-alpha; Doxorubicin; Oxidative Stress; Superoxide Dismutase; Myocardium; Antibiotics, Antineoplastic
PubMed: 36495663
DOI: 10.1016/j.biopha.2022.114055 -
PloS One 2023Doxorubicin, an anthracycline chemotherapeutic known to incur heart damage, decreases heart function in up to 11% of patients. Recent investigations have implicated the...
BACKGROUND
Doxorubicin, an anthracycline chemotherapeutic known to incur heart damage, decreases heart function in up to 11% of patients. Recent investigations have implicated the Wnt signaling cascade as a key modulator of cardiac tissue repair after myocardial infarction. Wnt upregulation in murine models resulted in stimulation of angiogenesis and suppression of fibrosis after ischemic insult. However, the molecular mechanisms of Wnt in mitigating doxorubicin-induced cardiac insult require further investigation. Identifying cardioprotective mechanisms of Wnt is imperative to reducing debilitating cardiovascular adverse events in oncologic patients undergoing treatment.
METHODS
Exposing human cardiomyocyte AC16 cells to varying concentrations of Wnt10b and DOX, we observed key metrics of cell viability. To assess the viability and apoptotic rates, we utilized MTT and TUNEL assays. We quantified cell and mitochondrial membrane stability via LDH release and JC-1 staining. To investigate how Wnt10b mitigates doxorubicin-induced apoptosis, we introduced pharmacologic inhibitors of key enzymes involved in apoptosis: FR180204 and SB203580, ERK1/2 and p38 inhibitors. Further, we quantified apoptotic executor enzymes, caspase 3/7, via immunofluorescence.
RESULTS
AC16 cells exposed solely to doxorubicin were shrunken with distorted morphology. Cardioprotective effects of Wnt10b were demonstrated via a reduction in apoptosis, from 70.1% to 50.1%. LDH release was also reduced between doxorubicin and combination groups from 2.27-fold to 1.56-fold relative to the healthy AC16 control group. Mitochondrial membrane stability was increased from 0.67-fold in the doxorubicin group to 5.73 in co-treated groups relative to control. Apoptotic protein expression was stifled by Wnt10b, with caspase3/7 expression reduced from 2.4- to 1.3-fold, and both a 20% decrease in p38 and 40% increase in ERK1/2 activity.
CONCLUSION
Our data with the AC16 cell model demonstrates that Wnt10b provides defense mechanisms against doxorubicin-induced cardiotoxicity and apoptosis. Further, we explain a mechanism of this beneficial effect involving the mitochondria through simultaneous suppression of pro-apoptotic p38 and anti-apoptotic ERK1/2 activities.
Topics: Animals; Humans; Mice; Antibiotics, Antineoplastic; Apoptosis; Cardiotoxicity; Doxorubicin; Myocytes, Cardiac; Oxidative Stress; Wnt Proteins
PubMed: 37856516
DOI: 10.1371/journal.pone.0277747 -
Lipids in Health and Disease Sep 2022Doxorubicin (DOX) is an anthracycline antibiotic frequently used against a wide range of cancers, including breast cancer. Although the drug is effective as a treatment... (Review)
Review
Doxorubicin (DOX) is an anthracycline antibiotic frequently used against a wide range of cancers, including breast cancer. Although the drug is effective as a treatment against cancer, many patients develop heart failure (HF) months to years following their last treatment with DOX. The challenge in preventing DOX-induced cardiotoxicity is that symptoms present after damage has already occurred in the myocardium. Therefore, early biomarkers to assess DOX-induced cardiotoxicity are urgently needed. A better understanding of the mechanisms involved in the toxicity is important as this may facilitate the development of novel early biomarkers or therapeutic approaches. In this review, we discuss the role of high-density lipoprotein (HDL) particles and its components as possible key players in the early development of DOX-induced cardiotoxicity. HDL particles exist in different subclasses which vary in composition and biological functionality. Multiple cardiovascular risk factors are associated with a change in HDL subclasses, resulting in modifications of their composition and physiological functions. There is growing evidence in the literature suggesting that cancer affects HDL subclasses and that healthy HDL particles enriched with sphingosine-1-phosphate (S1P) and apolipoprotein A1 (ApoA1) protect against DOX-induced cardiotoxicity. Here, we therefore discuss associations and relationships between HDL, DOX and cancer and discuss whether assessing HDL subclass/composition/function may be considered as a possible early biomarker to detect DOX-induced cardiotoxicity.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Breast Neoplasms; Cardiotoxicity; Doxorubicin; Female; Humans; Lipoproteins, HDL; Myocardium
PubMed: 36050733
DOI: 10.1186/s12944-022-01694-y -
Vascular Health and Risk Management 2022Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial...
BACKGROUND
Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial deterioration, and direct repression of muscle-specific gene expression. Adriamycin (Doxorubicin) is a potent anti-cancer agent. Adriamycin in prolonged use is fatal and generates free radicals that lead to dose-dependent cardiac toxicity.
OBJECTIVE
The intent of the study was to explore the protective activity of candesartan and quercetin in cardiomyopathy induced by doxorubicin in rats.
METHODS
To induce cardiac toxicity, rats were intraperitoneally treated with doxorubicin (06 equivalent injections of 2.5 mg/kg, i. p. at 48 hour interval for 02 consecutive weeks to achieve a cumulative dose of 15 mg/kg). Individual and combined oral treatment of candesartan (5 mg/kg/day) and quercetin (10 mg/kg/day) was administered for four weeks.
RESULTS
Following cardiomyopathy, heart/body weight ratio (3.526 × 10), serum creatine kinase (352.4±16.99 IU/L), lactate dehydrogenase (661.7±20.45 IU/L) levels were elevated in addition to altered lipid profile (TC - 118.4±4.25 mg/dL, TG - 263.3±9.99 mg/dL, VLDL - 52.66±1.99 mg/dL, LDL - 52.99±5.80 mg/dL and HDL - 12.78±0.36 mg/dL). The pre-cotreatment of candesartan and quercetin significantly restored the values to normal. The increased level of lipid peroxides (33.12±1.63 µmol/mg protein), serum troponin-T (1.82 ± 0.11 pg/mL) and nitric oxide (13.33±0.73 nmol/mg protein) level along with attenuating antioxidant profile, ie catalase, glutathione and superoxide dismutase (1.43±0.12 nmol/mg protein, 8.48±0.42 nmol/mg protein and 2.09±0.031 U/mg protein) were reversed to normal. Morphometry and histopathologic changes represented a beneficial effect of single and combination pre-cotreatment of drugs which significantly decreases adriamycin cardiac toxicity.
CONCLUSION
The overall result depicts more beneficial and cardioprotective effect of quercetin and candesartan combination as compared to their individual effects in doxorubicin treated animals. Therefore, this combination might be a suitable option to treat the cardiotoxic effect of doxorubicin.
Topics: Humans; Rats; Animals; Cardiotoxicity; Quercetin; Doxorubicin; Myocardium; Antioxidants; Antibiotics, Antineoplastic; Cardiomyopathies; Oxidative Stress
PubMed: 36536768
DOI: 10.2147/VHRM.S381485 -
Toxicology and Applied Pharmacology Jan 2023The anthracyclines are a family of natural products isolated from soil bacteria with over 2000 chemical representatives. Since their discovery seventy years ago by... (Review)
Review
The anthracyclines are a family of natural products isolated from soil bacteria with over 2000 chemical representatives. Since their discovery seventy years ago by Waksman and co-workers, anthracyclines have become one of the best-characterized anticancer chemotherapies in clinical use. The anthracyclines exhibit broad-spectrum antineoplastic activity for the treatment of a variety of solid and liquid tumors, however, their clinical use is limited by their dose-limiting cardiotoxicity. In this review article, we discuss the toxicity of the anthracyclines on several organ systems, including new insights into doxorubicin-induced cardiotoxicity. In addition, we discuss new medicinal chemistry developments in the biosynthesis of new anthracycline analogs and the synthesis of new anthracycline analogs with diminished cardiotoxicity. Lastly, we review new studies that describe the repurposing of the anthracyclines, or "upcycling" of the anthracyclines, as anti-infective agents, or drugs for niche indications. Altogether, the anthracyclines remain a mainstay in the clinic with a potential new "lease on life" due to deeper insight into the mechanism underlying their cardiotoxicity and new developments into potential new clinical indications for their use. Keywords: Anthracycline, chemotherapy, toxicology, medicinal chemistry, biosynthesis.
Topics: Humans; Anthracyclines; Cardiotoxicity; Antibiotics, Antineoplastic; Antineoplastic Agents; Doxorubicin
PubMed: 36592899
DOI: 10.1016/j.taap.2022.116362 -
FASEB Journal : Official Publication of... Jun 2023Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of...
Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline-induced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systems-level transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human-induced pluripotent stem cell-derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of Igfbp-3 in cardiomyocytes. Furthermore, Igfbp-3 reduces DNA damage, impedes topoisomerase IIβ expression (Top2β) which forms Top2β-Dox-DNA cleavage complex leading to DNA double-strand breaks (DSB), alleviates detyrosinated microtubule accumulation-a hallmark of increased cardiomyocyte stiffness and heart failure-and favorably affects contractility following Dox treatment. These results indicate that Igfbp-3 is induced by cardiomyocytes in an effort to mitigate AIC.
Topics: Humans; Animals; Rats; Anthracyclines; Transcriptome; Cardiotoxicity; Antibiotics, Antineoplastic; Myocytes, Cardiac
PubMed: 37219486
DOI: 10.1096/fj.202201885RR