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Naunyn-Schmiedeberg's Archives of... Jun 2024The current study compared the effects of incorporated exposure to arsenic trioxide (As) and zinc oxide nanoparticles (ZnONPs) on male reproductive hormones, oxidative...
Mitigating effect of gallic acid on zinc oxide nanoparticles and arsenic trioxide-induced spermatogenesis suppression, testicular injury, hormonal imbalance, and immunohistochemical changes in rats.
The current study compared the effects of incorporated exposure to arsenic trioxide (As) and zinc oxide nanoparticles (ZnONPs) on male reproductive hormones, oxidative stress, and inflammatory biomarkers in adult rats to each metal alone. A defensive trial with gallic acid (GA) has also been studied. A total of 60 adult male Sprague Dawley rats were categorized into six groups: control, GA (20 mg/kg), ZnONPs (100 mg/kg), As (8 mg/kg), ZnONPs with As, and GA concurrently with ZnONPs and As at the same previous doses. The regimens were applied for 60 days in sequence. Current findings showed significant weight loss in all study groups, with testicular weights significantly decreased in the As and combined groups. Testosterone, follicular stimulating hormone, and luteinizing hormone serum levels were also considerably reduced, while serum levels of estradiol increased. Inducible nitric oxide synthase (iNOS) immunoexpression was significantly upregulated while proliferating cell nuclear antigen (PCNA) was downregulated. Moreover, there was a significant elevation of testicular malondialdehyde, reduction of testicular superoxide dismutase, and glutathione peroxidase with disruptive testes, prostate glands, and seminal vesicle alterations in all experimental groups with marked changes in the combined group. Additionally, the present results revealed the protective effects of GA on ZnONPs and As adverse alterations in rats. GA enhanced sperm picture, oxidant status, and hormonal profile. Also, it modulates iNOS and PCNA immunoexpression and recovers the histoarchitecture of the testes, prostate glands, and seminal vesicles. Ultimately, GA may be a promising safeguarding agent against ZnONPs and As-induced disturbances to reproductive parameters.
PubMed: 38935127
DOI: 10.1007/s00210-024-03228-y -
International Journal of Molecular... Jun 2024All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread... (Review)
Review
All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.
Topics: Humans; Retinoic Acid Receptor gamma; Receptors, Retinoic Acid; Animals; Tretinoin; Protein Binding; Leukemia, Promyelocytic, Acute; Antineoplastic Agents
PubMed: 38928275
DOI: 10.3390/ijms25126568 -
Hematology Reports Jun 2024Acute promyelocytic leukemia is a rare form of acute myeloid leukemia in which immature promyelocytes abnormally proliferate in the bone marrow. In most cases, the...
Acute promyelocytic leukemia is a rare form of acute myeloid leukemia in which immature promyelocytes abnormally proliferate in the bone marrow. In most cases, the disease is characterised by the translocation t(15;17) (q24;q21), which causes the formation of PML::RARA, an oncogenic fusion protein responsible for blocking myeloid differentiation and survival advantage. Here, we present a case of acute promyelocytic leukemia with two unusual features: basophilic differentiation and a three-way translocation involving chromosomes 12, 15 and 17. In the few cases reported, basophilic differentiation was associated with a poor prognosis. In contrast, our patient responded promptly to the standard treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) and obtained complete remission. To our knowledge, this is the first report of basophilic acute promyelocytic leukemia with the three-way translocation t(12;17;15) (p13; q24;q21).
PubMed: 38921185
DOI: 10.3390/hematolrep16020037 -
Expert Opinion on Drug Delivery Jun 2024Arsenicals have a special place in the history of human health, acting both as poison and medicine. Having been used to treat a variety of diseases in the past, the... (Review)
Review
INTRODUCTION
Arsenicals have a special place in the history of human health, acting both as poison and medicine. Having been used to treat a variety of diseases in the past, the success of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) in the last century marked its use as a drug in modern medicine. To expand their role against cancer, there have been clinical uses of arsenicals worldwide and progress in the development of drug delivery for various malignancies, especially solid tumors.
AREAS COVERED
In this review, conducted on Google Scholar [1977-2024], we start with various forms of arsenicals, highlighting the well-known ATO. The mechanism of action of arsenicals in cancer therapy is then overviewed. A summary of the research progress in developing new delivery approaches (e.g. polymers, inorganic frameworks, and biomacromolecules) in recent years is provided, addressing the challenges and opportunities in treating various malignant tumors.
EXPERT OPINION
Reducing toxicity and enhancing therapeutic efficacy are guidelines for designing and developing new arsenicals and drug delivery systems. They have shown potential in the fight against cancer and emerging pathogens. New technologies and strategies can help us harness the potency of arsenicals and make better products.
PubMed: 38913024
DOI: 10.1080/17425247.2024.2372363 -
Environmental Pollution (Barking, Essex... Jun 2024To explore the characteristics and evaluate the risk of heavy metals in groundwater at a typical smelter-contaminated site, this study focuses on a representative a...
To explore the characteristics and evaluate the risk of heavy metals in groundwater at a typical smelter-contaminated site, this study focuses on a representative a historical arsenic smelting plant in Southwest China, where the primary historical products were metallic arsenic (∼1000 tons/year) and arsenic trioxide (∼2000 ton/year). The results demonstrated As and Pb as the main pollutants in soil, and As and Cd as main pollutants in groundwater through soil profiling and quarterly groundwater analysis. The maximum As and Pb in the surface soil were 76800 and 2290 mg/kg, respectively, with As vertically infiltrating the deep gravel-sand layer (18-20 m). The groundwater pollution distribution progressively increased along flow direction, influenced by seasonal surface runoff and infiltration fluctuations. The groundwater pollutant concentrations during the dry season notably surpassed those during the wet season, with maximum As and Cd concentrations of 111.64 mg/L and 19.85 μg/L during the dry season, respectively. Furthermore, the analytic hierarchy process (AHP) was applied to evaluate the comprehensive risk of contaminated-site across pollution source load, regional groundwater intrinsic vulnerability, and evaluation of nearby sensitive receptors. The results revealed that the carcinogenic risk of lead in surface soil was moderate to high, while arsenic posed a high carcinogenic risk, contributing to an overall carcinogenic risk proportion of 89.6% in surface soil. Exposure through groundwater intake was identified as the primary pathway, with carcinogenic and noncarcinogenic risks exceeding those through skin contact. The final weights result demonstrated that the principal risk factors are the intrinsic arsenic load and protective target characteristics of regional groundwater at this site. This study provides a reference for comprehensive assessments of similarly contaminated industrial and smelting sites.
PubMed: 38906401
DOI: 10.1016/j.envpol.2024.124401 -
Cureus May 2024The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal...
Acute Promyelocytic Leukemia With Long and Short Isoforms of PML::RARA Fusion Transcripts Complicated by Abdominal Distension and Acute Edematous Pancreatitis During Induction Treatment: A Case Report.
The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal disease to one of the most curable human malignancies in recent decades. However, early mortality caused by coagulopathy, infection, multi-organ failure, and differentiation syndrome (DS) during disease onset and induction treatment remains a major issue in APL, especially in elderly patients who may suffer from higher treatment-related mortality due to a higher vulnerability to treatment toxicities. Herein, we present a case of an elderly patient with APL with rare mixed long (L-) and short (S-) isoforms of PML::RARA fusion transcripts who had multiple complications at disease onset. In addition, the initiation of treatment with ATRA in combination with ATO led to the rapid onset of severe DS. In particular, this patient experienced a rare clinical feature of DS, acute edematous pancreatitis (AEP). Furthermore, due to the patient's refractory abdominal distension related to the dose of ATRA, ATO, and Realgar-Indigo Naturalis Formula (RIF), we have to repeatedly adjust the doses of these drugs that the patient can maximally tolerate. Nevertheless, the patient achieved complete remission (CR) even after receiving a substandard dose of these drugs. However, the patient relapsed, acquired the FLT3-ITD mutation nine months later, and experienced abdominal distension again while receiving the standard doses of ATRA and RIF. Therefore, these drugs were adjusted to the maximum tolerated dose based on the experience with the initial induction treatment, and the patient achieved CR after four weeks of reinduction treatment. We report that this case may provide some clinical information for the diagnosis and treatment of similar patients with APL.
PubMed: 38883104
DOI: 10.7759/cureus.60321 -
Scientific Reports Jun 2024Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective...
Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90-100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.
Topics: Humans; Fenretinide; Leukemia, Promyelocytic, Acute; HL-60 Cells; Apoptosis; Reactive Oxygen Species; Antineoplastic Agents; Nanoparticles; Cell Survival; Micelles; Membrane Potential, Mitochondrial
PubMed: 38877119
DOI: 10.1038/s41598-024-64629-w -
International Journal of Laboratory... Jun 2024In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the...
INTRODUCTION
In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL.
METHODS
In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen.
RESULTS
The median follow-up period was 63.0 months. CD117 was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117 subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117 APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively).
CONCLUSIONS
To sum up, CD117 is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.
PubMed: 38874282
DOI: 10.1111/ijlh.14326 -
Translational Oncology Aug 2024New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target...
New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target for new drugs for this disease. Arsenic trioxide (ATO), which is used to treat promyelocytic leukaemia, was recently shown to reactivate mutant p53 and restore wild-type functionality. The aim of this study was to evaluate ATO as a potential new treatment for TNBC. Using a panel of 20 cell lines, we found that TNBC cell lines were more sensitive to ATO than non-TNBC cell lines (P = 0.045). Consistent with its ability to reactivate mutant p53, ATO was a more potent inhibitor of proliferation in cell lines with mutant TP53 than the wildtype TP53 (P = 0.027). Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, BBC3, PMAIP1, SESN2, SRXN1 and TXNRD1. Our findings support the activation of mutant p53 by ATO and, furthermore, the possible repurposing of ATO to treat TP53-mutated TNBC.
PubMed: 38870678
DOI: 10.1016/j.tranon.2024.102025 -
Cell Death & Disease Jun 2024The cavity-creating p53 cancer mutation Y220C is an ideal paradigm for developing small-molecule drugs based on protein stabilization. Here, we have systematically...
The cavity-creating p53 cancer mutation Y220C is an ideal paradigm for developing small-molecule drugs based on protein stabilization. Here, we have systematically analyzed the structural and stability effects of all oncogenic Tyr-to-Cys mutations (Y126C, Y163C, Y205C, Y220C, Y234C, and Y236C) in the p53 DNA-binding domain (DBD). They were all highly destabilizing, drastically lowering the melting temperature of the protein by 8-17 °C. In contrast, two non-cancerous mutations, Y103C and Y107C, had only a moderate effect on protein stability. Differential stabilization of the mutants upon treatment with the anticancer agent arsenic trioxide and stibogluconate revealed an interesting proximity effect. Crystallographic studies complemented by MD simulations showed that two of the mutations, Y234C and Y236C, create internal cavities of different size and shape, whereas the others induce unique surface lesions. The mutation-induced pockets in the Y126C and Y205C mutant were, however, relatively small compared with that of the already druggable Y220C mutant. Intriguingly, our structural studies suggest a pronounced plasticity of the mutation-induced pocket in the frequently occurring Y163C mutant, which may be exploited for the development of small-molecule stabilizers. We point out general principles for reactivating thermolabile cancer mutants and highlight special cases where mutant-specific drugs are needed for the pharmacological rescue of p53 function in tumors.
Topics: Tumor Suppressor Protein p53; Humans; Mutation; Neoplasms; Arsenic Trioxide; Molecular Dynamics Simulation; Protein Stability; Antineoplastic Agents
PubMed: 38862470
DOI: 10.1038/s41419-024-06739-x