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Cancers Jun 2024Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian... (Review)
Review
Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian reserve suppression and estrogen deficiency result in reduced quality of life for cancer patients and are frequently the cause of infertility and early menopause. Classic alkylating cytostatics are among the most toxic chemotherapeutics in this regard. They cause DNA damage in ovarian follicles and the cells they contain, and they can also induce oxidative stress or affect numerous signaling pathways. In vitro tests, animal models, and a few studies among women have investigated the effects of various agents on the protection of the ovarian reserve during classic chemotherapy. In this review article, we focused on the possible beneficial effects of selected hormones (anti-Müllerian hormone, ghrelin, luteinizing hormone, melatonin), agents affecting the activity of apoptotic pathways and modulating gene expression (C1P, S1P, microRNA), and several natural (quercetin, rapamycin, resveratrol) and synthetic compounds (bortezomib, dexrazoxane, goserelin, gonadoliberin analogs, imatinib, metformin, tamoxifen) in preventing gynotoxic effects induced by commonly used cytostatics. The presented line of research appears to provide a promising strategy for protecting and/or improving the ovarian reserve in the studied group of cancer patients. However, well-designed clinical trials are needed to unequivocally assess the effects of these agents on improving hormonal function and fertility in women treated with ovotoxic anticancer drugs.
PubMed: 38927992
DOI: 10.3390/cancers16122288 -
Advanced Drug Delivery Reviews Jun 2024Every year, more than a million people in the United States undergo chemotherapy or radiation therapy for cancer, as estimated by the CDC. While chemotherapy has been an... (Review)
Review
Every year, more than a million people in the United States undergo chemotherapy or radiation therapy for cancer, as estimated by the CDC. While chemotherapy has been an instrumental tool for treating cancer, it also causes severe adverse effects. The more commonly acknowledged adverse effects include hair loss, fatigue, and nausea, but a more severe and longer lasting side effect is cardiotoxicity. Cardiotoxicity, or heart damage, is a common complication of cancer treatments. It can range from mild to severe, and it can affect some patients temporarily or others permanently, even after they are cured of cancer. Dexrazoxane is the only FDA-approved drug for treating anthracycline induced cardiotoxicity, but it also has drawbacks and adverse effects. There is no other type of chemotherapy induced cardiotoxicity that has an approved treatment option. In this review, we discuss the pathophysiology of chemotherapeutic-induced cardiotoxicity, methods and guidelines of diagnosis, methods of treatment and mitigation, and current drug delivery approaches in therapeutic development.
PubMed: 38901637
DOI: 10.1016/j.addr.2024.115361 -
Chemico-biological Interactions May 2024Oleic acid (OA) is a monounsaturated compound with many health-benefitting properties such as obesity prevention, increased insulin sensitivity, antihypertensive and...
Oleic acid (OA) is a monounsaturated compound with many health-benefitting properties such as obesity prevention, increased insulin sensitivity, antihypertensive and immune-boosting properties, etc. The aim of this study was to analyze the effect of oleic acid (OA) and some anticancer drugs against oxidative damage induced by nitropropionic acid (NPA) in rat brain. Six groups of Wistar rats were treated as follows: Group 1, (control); group 2, OA; group 3, NPA + OA; group 4, cyclophosphamide (CPP) + OA; group 5, daunorubicin (DRB) + OA; and group 6, dexrazoxane (DXZ) + OA. All compounds were administered intraperitoneally route, every 24 h for 5 days. Their brains were extracted to measure lipoperoxidation (TBARS), HO, Ca, Mg ATPase activity, glutathione (GSH) and dopamine. Glucose, hemoglobin and triglycerides were measured in blood. In cortex GSH increased in all groups, except in group 2, the group 4 showed the highest increase of this biomarker. TBARS decrease, and dopamine increase in all regions of groups 4, 5 and 6. HO increased only in cerebellum/medulla oblongata of group 5 and 6. ATPase expression decreased in striatum of group 4. Glucose increased in group 6, and hemoglobin increased in groups 4 and 5. These results suggest that the increase of dopamine and the antioxidant effect of oleic acid administration during treatment with oncologic agents could result in less brain injury.
PubMed: 38825054
DOI: 10.1016/j.cbi.2024.111086 -
Microorganisms May 2024Antibiotic resistance is a global health crisis. Notably, carbapenem-resistant Enterobacterales (CRE) pose a significant clinical challenge due to the limited effective...
Antibiotic resistance is a global health crisis. Notably, carbapenem-resistant Enterobacterales (CRE) pose a significant clinical challenge due to the limited effective treatment options. This problem is exacerbated by persisters that develop upon antibiotic exposure. Bacteria persisters can tolerate high antibiotic doses and can cause recalcitrant infections, potentially developing further antibiotic resistance. Iron is a critical micronutrient for survival. We aimed to evaluate the utility of iron chelators, alone and in combination with antibiotics, in managing persisters. We hypothesized that iron chelators eradicate CRE persisters in vitro, when administered in combination with antibiotics. Our screening revealed three clinical isolates with bacteria persisters that resuscitated upon antibiotic removal. These isolates were treated with both meropenem and an iron chelator (deferoxamine mesylate, deferiprone or dexrazoxane) over 24 h. Against our hypothesis, bacteria persisters survived and resuscitated upon withdrawing both the antibiotic and iron chelator. Pursuing our aim, we next hypothesized that iron chelation is feasible as a post-antibiotic treatment in managing and suppressing persisters' resuscitation. We exposed bacteria persisters to an iron chelator without antibiotics. Flow cytometric assessments revealed that iron chelators are inconsistent in suppressing persister resuscitation. Collectively, these results suggest that the iron chelation strategy may not be useful as an antibiotic adjunct to target planktonic bacteria persisters.
PubMed: 38792801
DOI: 10.3390/microorganisms12050972 -
The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites.International Journal of Molecular... May 2024Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic... (Review)
Review
Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75-100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.
Topics: Humans; Aspirin; Anemia, Iron-Deficiency; Iron; Iron Chelating Agents; Salicylic Acid; Gentisates; Hippurates; Hydroxybenzoates
PubMed: 38791185
DOI: 10.3390/ijms25105150 -
JACC. CardioOncology Apr 2024
PubMed: 38774009
DOI: 10.1016/j.jaccao.2024.01.004 -
JACC. CardioOncology Apr 2024Older patients with Hodgkin lymphoma (HL) often have comorbid cardiovascular disease; however, the impact of pre-existing heart failure (HF) on the management and...
BACKGROUND
Older patients with Hodgkin lymphoma (HL) often have comorbid cardiovascular disease; however, the impact of pre-existing heart failure (HF) on the management and outcomes of HL is unknown.
OBJECTIVES
The aim of this study was to assess the prevalence of pre-existing HF in older patients with HL and its impact on treatment and outcomes.
METHODS
Linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data from 1999 to 2016 were used to identify patients 65 years and older with newly diagnosed HL. Pre-existing HF, comorbidities, and cancer treatment were ascertained from billing codes and cause-specific mortality from SEER. The associations between pre-existing HF and cancer treatment were estimated using multivariable logistic regression. Cause-specific Cox proportional hazards models adjusted for comorbidities and cancer treatment were used to estimate the association between pre-existing HF and cause-specific mortality.
RESULTS
Among 3,348 patients (mean age 76 ± 7 years, 48.6% women) with newly diagnosed HL, pre-existing HF was present in 437 (13.1%). Pre-existing HF was associated with a lower likelihood of using anthracycline-based chemotherapy regimens (OR: 0.42; 95% CI: 0.29-0.60) and a higher likelihood of lymphoma mortality (HR: 1.25; 95% CI: 1.06-1.46) and cardiovascular mortality (HR: 2.57; 95% CI: 1.96-3.36) in models adjusted for comorbidities. One-year lymphoma mortality cumulative incidence was 37.4% (95% CI: 35.5%-39.5%) with pre-existing HF and 26.3% (95% CI: 25.0%-27.6%) without pre-existing HF. The cardioprotective medications dexrazoxane and liposomal doxorubicin were used in only 4.2% of patients.
CONCLUSIONS
Pre-existing HF in older patients with newly diagnosed HL is common and associated with higher 1-year mortality. Strategies are needed to improve lymphoma and cardiovascular outcomes in this high-risk population.
PubMed: 38774008
DOI: 10.1016/j.jaccao.2024.02.003 -
JACC. CardioOncology Apr 2024
PubMed: 38773999
DOI: 10.1016/j.jaccao.2024.02.004 -
International Journal of Molecular... Apr 2024The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction... (Review)
Review
The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.
Topics: Humans; Iron Overload; Iron Chelating Agents; Anemia, Iron-Deficiency; Iron; Animals; Deferiprone
PubMed: 38731873
DOI: 10.3390/ijms25094654 -
Journal of the American Heart... May 2024The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So,...
BACKGROUND
The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure.
METHODS AND RESULTS
Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, =0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity.
CONCLUSIONS
Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.
Topics: Colchicine; Doxorubicin; Cardiotoxicity; Autophagy; Lysosomes; Animals; Myocytes, Cardiac; Disease Models, Animal; Male; Heart Failure; Antibiotics, Antineoplastic; Reactive Oxygen Species; Mice; Mice, Inbred C57BL; Ventricular Function, Left
PubMed: 38700005
DOI: 10.1161/JAHA.123.033700