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International Journal of Biological... 2022Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its... (Review)
Review
Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.
Topics: Acute Disease; Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Cell Death; Doxorubicin; Humans; Neoplasms; Oxidative Stress
PubMed: 35002523
DOI: 10.7150/ijbs.65258 -
Circulation Research Mar 2020Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly... (Review)
Review
Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiomyopathies; Doxorubicin; Humans; Mitochondria, Heart; Mitophagy; Reactive Oxygen Species; Superoxides
PubMed: 32213135
DOI: 10.1161/CIRCRESAHA.119.314681 -
Journal of Clinical Oncology : Official... Nov 2021Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm,...
PURPOSE
Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor -sirolimus (AMPECT, NCT02494570).
PATIENTS AND METHODS
Patients with malignant PEComa were treated with -sirolimus 100 mg/m intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis.
RESULTS
Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a mutation achieved a confirmed response versus 2 of 16 (13%) without mutation ( < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred.
CONCLUSION
-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that -sirolimus represents an important new treatment option for this disease.
Topics: Adult; Aged; Albumins; Antibiotics, Antineoplastic; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nanoparticles; Neoplasm Metastasis; Perivascular Epithelioid Cell Neoplasms; Prognosis; Prospective Studies; Sirolimus; Survival Rate
PubMed: 34637337
DOI: 10.1200/JCO.21.01728 -
Journal of Cancer Research and... 2014The burden of cancer is continuously increasing, and is rapidly becoming a global pandemic. The first liposomal encapsulated anticancer drug which received clinical... (Review)
Review
The burden of cancer is continuously increasing, and is rapidly becoming a global pandemic. The first liposomal encapsulated anticancer drug which received clinical approval against malignancies including solid tumours, transplantable leukemias and lymphomas was Doxorubicin HCl. This review is aimed at providing an overview of doxorubicin in cancer therapy. Pegylated liposomal doxorubicin has a polyethylene glycol (PEG) layer around doxorubicin-containing liposome as the result of a process known as pegylation. Non-pegylated liposomal doxorubicin (NPLD) was developed to overcome the drawbacks associated with previous formulations. Nudoxa; (NPLD) with its unique drug delivery system offers the benefit of pegylated liposomal doxorubicin without hand foot syndrome as the major side effect. Future studies will be directed towards estimating the costs of treatment with the novel liposomal doxorubicin formulations in order to assess their widespread use and robustness in treating patients with cancer.
Topics: Antibiotics, Antineoplastic; Doxorubicin; Humans; Neoplasms; Polyethylene Glycols
PubMed: 25579518
DOI: 10.4103/0973-1482.139267 -
Cell Mar 2017The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and...
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
Topics: Aging; Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle Proteins; Cell Line; Cell Survival; Cell-Penetrating Peptides; Cellular Senescence; Doxorubicin; Female; Fibroblasts; Forkhead Transcription Factors; Humans; Inclusion Bodies; Kidney; Liver; Male; Mice; Trichothiodystrophy Syndromes; Tumor Suppressor Protein p53
PubMed: 28340339
DOI: 10.1016/j.cell.2017.02.031 -
European Review For Medical and... Jan 2020To investigate the influences of rapamycin on proliferation and apoptosis of human osteosarcoma MG-63 cells and the mechanisms of action.
OBJECTIVE
To investigate the influences of rapamycin on proliferation and apoptosis of human osteosarcoma MG-63 cells and the mechanisms of action.
MATERIALS AND METHODS
The human osteosarcoma MG-63 cells were randomly divided into Control group, Rapamycin group, and Rapamycin + Beclin-1 plasmid transfection group. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was adopted to detect the viability of MG-63 cells in each group, and the 5-Ethynyl-2'-deoxyuridine (EdU) staining and Hoechst staining were applied to determine the proliferation and apoptosis, respectively, of MG-63 cells in each group. The levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were measured using enzyme-linked immunosorbent assay (ELISA) kits, and the protein expression levels of Beclin-1 and Vps34 in each group of MG-63 cells were tested using the Western blotting.
RESULTS
Compared with the Control group, Rapamycin group, and Rapamycin + Beclin-1 plasmid transfection group had markedly weakened the viability of MG-63 cells, inhibited cell proliferation, remarkably increased cell apoptosis rate, elevated Bax level, notably declined Bcl-2 level, and significantly raised the levels of Beclin-1 and Vps34 proteins in MG-63 cells. Besides, the effects in Beclin-1 plasmid transfection group were stronger.
CONCLUSIONS
Rapamycin may decrease the viability, inhibit the proliferation, and promote the apoptosis of MG-63 cells by activating autophagy.
Topics: Antibiotics, Antineoplastic; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Osteosarcoma; Random Allocation; Sirolimus
PubMed: 32016998
DOI: 10.26355/eurrev_202001_20076 -
BMC Cardiovascular Disorders Mar 2021Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been...
BACKGROUND
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
CASE PRESENTATION
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
CONCLUSIONS
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Topics: Antibiotics, Antineoplastic; Epirubicin; Humans; Iliac Artery; Injections, Intra-Arterial; Kounis Syndrome; Male; Middle Aged; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 33711934
DOI: 10.1186/s12872-021-01936-4 -
Clinical Science (London, England :... May 2021Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is... (Review)
Review
Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is associated with a significant risk of cardiovascular toxicities and may result in cardiomyopathy and heart failure. Cardiomyocyte toxicity occurs via multiple molecular mechanisms, including topoisomerase II-mediated DNA double-strand breaks and reactive oxygen species (ROS) formation via effects on the mitochondrial electron transport chain, NADPH oxidases (NOXs), and nitric oxide synthases (NOSs). Excess ROS may cause mitochondrial dysfunction, endoplasmic reticulum stress, calcium release, and DNA damage, which may result in cardiomyocyte dysfunction or cell death. These pathophysiologic mechanisms cause tissue-level manifestations, including characteristic histopathologic changes (myocyte vacuolization, myofibrillar loss, and cell death), atrophy and fibrosis, and organ-level manifestations including cardiac contractile dysfunction and vascular dysfunction. In addition, these mechanisms are relevant to current and emerging strategies to diagnose, prevent, and treat anthracycline-induced cardiomyopathy. This review details the established and emerging data regarding the molecular mechanisms of anthracycline-induced cardiovascular toxicity.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Cardiomyopathies; Cardiovascular System; Humans; Myocytes, Cardiac; Risk Factors
PubMed: 34047339
DOI: 10.1042/CS20200301 -
American Journal of Physiology. Heart... Jan 2019Cancer is the leading cause of morbidity and mortality in the United States and globally. Owing to improved early diagnosis and advances in oncological therapeutic... (Review)
Review
Cancer is the leading cause of morbidity and mortality in the United States and globally. Owing to improved early diagnosis and advances in oncological therapeutic options, the number of cancer survivors has steadily increased. Such efficient cancer therapies have also lead to alarming increase in cardiovascular complications in a significant proportion of cancer survivors, due to adverse cardiovascular effects such as cardiotoxicity, cardiac atrophy, and myocarditis. This has emerged as a notable concern in healthcare and given rise to the new field of cardioncology, which aims at understanding the processes that occur in the two distinct disorders and how they interact to influence the progression of each other. A key player in both cancer and heart failure is the genome, which is predominantly transcribed to noncoding RNAs (ncRNAs). Since the emergence of ncRNAs as master regulators of gene expression, several reports have shown the relevance of ncRNAs in cancer and cardiovascular disorders. However, the knowledge is quite limited regarding the relevance of ncRNAs in cardioncology. The objective of this review is to summarize the current knowledge of ncRNAs in the context of cardioncology. Furthermore, the therapeutic strategies as well as the prospective translational applications of these ncRNA molecules to the clinics are also discussed.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Doxorubicin; Heart Failure; Humans; MicroRNAs; RNA, Long Noncoding
PubMed: 30412441
DOI: 10.1152/ajpheart.00418.2018 -
Biomedicine & Pharmacotherapy =... Sep 2021Tranilast (TRN) or (N-3,4 -dimethoxy cinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite and is identified mainly as an anti-allergic agent with limited... (Review)
Review
Tranilast (TRN) or (N-3,4 -dimethoxy cinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite and is identified mainly as an anti-allergic agent with limited side effects. The anti-cancer effects of tranilast either alone or in combination with chemotherapeutic drugs have been evidenced in several pre-clinical studies. The main mechanism of action of tranilast includes targeting and modulation of various signaling and immune regulatory pathways including Transforming growth factor-beta (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol 3-kinase (PI3K), MAP-Kinase (MAPK), Protein kinase B (Akt/PKB), c-Jun N-terminal kinase, modulation of cancer stem cells, etc. Most of these pathways are involved in tumor proliferation, invasion, and metastasis and it is postulated that tranilast, with its low toxicity profile and high anti-carcinogenic abilities, can serve as a potential anti-tumorigenic agent. The main aim of this review is to provide updated information on the anti-cancer effects of tranilast and its significance as a therapeutic agent.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Humans; Neoplasms; Signal Transduction; ortho-Aminobenzoates
PubMed: 34174504
DOI: 10.1016/j.biopha.2021.111844