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3 Biotech Apr 2023Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer...
UNLABELLED
Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer considerable translational applicability, as a permanent regression process may be therapeutically replicated on patients. For this, we developed a systems biological formulation of the regression process with experimental verification and identified the relevant candidate biomolecules for therapeutic utility. We devised a cellular kinetics-based quantitative model of tumor extinction in terms of the temporal behavior of three main tumor-lysis entities: DNA blockade factor, cytotoxic T-lymphocyte and interleukin-2. As a case study, we analyzed the time-wise biopsy and microarrays of spontaneously regressing melanoma and fibrosarcoma tumors in mammalian/human hosts. We analyzed the differentially expressed genes (DEGs), signaling pathways, and bioinformatics framework of regression. Additionally, prospective biomolecules that could cause complete tumor regression were investigated. The tumor regression process follows a first-order cellular dynamics with a small negative bias, as verified by experimental fibrosarcoma regression; the bias is necessary to eliminate the residual tumor. We identified 176 upregulated and 116 downregulated DEGs, and enrichment analysis showed that the most significant were downregulated cell-division genes: TOP2A-KIF20A-KIF23-CDK1-CCNB1. Moreover, Topoisomerase-IIA inhibition might actuate spontaneous regression, with collateral confirmation provided from survival and genomic analysis of melanoma patients. Candidate molecules such as Dexrazoxane/Mitoxantrone, with interleukin-2 and antitumor lymphocytes, may potentially replicate permanent tumor regression process of melanoma. To conclude, episodic permanent tumor regression is a unique biological reversal process of malignant progression, and signaling pathway understanding, with candidate biomolecules, may plausibly therapeutically replicate the regression process on tumors clinically.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-023-03515-0.
PubMed: 36890970
DOI: 10.1007/s13205-023-03515-0 -
Scientific Reports Feb 2021The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical...
Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity.
The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.
Topics: Animals; Anthracyclines; Cardiotonic Agents; Cardiotoxicity; DNA Topoisomerases, Type II; Dexrazoxane; Diketopiperazines; Male; Myocytes, Cardiac; Piperazine; Prodrugs; Rabbits; Razoxane; Topoisomerase II Inhibitors; Water
PubMed: 33627707
DOI: 10.1038/s41598-021-83688-x -
Archives of Toxicology Jul 2021The majority of drug candidates fails the approval phase due to unwanted toxicities and side effects. Establishment of an effective toxicity prediction platform is of...
The majority of drug candidates fails the approval phase due to unwanted toxicities and side effects. Establishment of an effective toxicity prediction platform is of utmost importance, to increase the efficiency of the drug discovery process. For this purpose, we developed a toxicity prediction platform with machine-learning strategies. Cardiotoxicity prediction was performed by establishing a model with five parameters (arrhythmia, cardiac failure, heart block, hypertension, myocardial infarction) and additional toxicity predictions such as hepatotoxicity, reproductive toxicity, mutagenicity, and tumorigenicity are performed by using Data Warrior and Pro-Tox-II software. As a case study, we selected artemisinin derivatives to evaluate the platform and to provide a list of safe artemisinin derivatives. Artemisinin from Artemisia annua was described first as an anti-malarial compound and later its anticancer properties were discovered. Here, random forest feature selection algorithm was used for the establishment of cardiotoxicity models. High AUC scores above 0.830 were achieved for all five cardiotoxicity indications. Using a chemical library of 374 artemisinin derivatives as a case study, 7 compounds (deoxydihydro-artemisinin, 3-hydroxy-deoxy-dihydroartemisinin, 3-desoxy-dihydroartemisinin, dihydroartemisinin-furano acetate-d3, deoxyartemisinin, artemisinin G, artemisinin B) passed the toxicity filtering process for hepatotoxicity, mutagenicity, tumorigenicity, and reproductive toxicity in addition to cardiotoxicity. Experimental validation with the cardiomyocyte cell line AC16 supported the findings from the in silico cardiotoxicity model predictions. Transcriptomic profiling of AC16 cells upon artemisinin B treatment revealed a similar gene expression profile as that of the control compound, dexrazoxane. In vivo experiments with a Zebrafish model further substantiated the in silico and in vitro data, as only slight cardiotoxicity in picomolar range was observed. In conclusion, our machine-learning approach combined with in vitro and in vivo experimentation represents a suitable method to predict cardiotoxicity of drug candidates.
Topics: Animals; Artemisinins; Cardiotoxicity; Machine Learning; Software; Zebrafish
PubMed: 34021777
DOI: 10.1007/s00204-021-03058-4 -
PloS One 2023[This corrects the article DOI: 10.1371/journal.pone.0294848.].
[This corrects the article DOI: 10.1371/journal.pone.0294848.].
PubMed: 38117773
DOI: 10.1371/journal.pone.0296372 -
Cadernos de Saude Publica Sep 2019Cancer in individuals 0 to 19 years of age is considered rare when compared to incidence in older age brackets, and is estimated at 2% to 3% of all malignant tumors...
Cancer in individuals 0 to 19 years of age is considered rare when compared to incidence in older age brackets, and is estimated at 2% to 3% of all malignant tumors recorded in Brazil. The use of anthracyclines is frequently associated with cardiotoxicity, and these drugs are part of approximately 60% of treatment protocols in pediatric oncology. Among the existing strategies for the prevention of cardiotoxicity, dexrazoxane obtained favorable results based on intermediate outcomes (biochemical markers and echocardiographic parameters). This study was based on a cost-effectiveness assessment comparing the use of dexrazoxane in different populations, besides an assessment of the budget impact from the technology's potential incorporation. The patient's lifetime was used as the timeline, and the analysis was performed from the perspective of the Brazilian Unified National Health System (SUS). A budget impact analysis was also performed for each technology. After a literature search, a Markov model was developed, capable of comparing the use of dexrazoxane in six profiles of patients at risk of developing cardiotoxicity. Use of the drug in children under 5 years of age proved to be the most cost-effective alternative (incremental cost effectiveness ratio - ICER of BRL 6,156.96), followed by use in all patients (ICER of BRL 58,968.70). If the price decreased to less than BRL 250.00 per vial, the alternative of using the drug in all children would become the most cost-effective. The budget impact at 5 years was BRL 30,622,404.81 for use only in children under 5 years of age. Using the technology in all the children could produce an incremental impact of BRL 94,352,898.77.
Topics: Age Factors; Anthracyclines; Cardiotonic Agents; Cardiotoxicity; Child; Child, Preschool; Cost-Benefit Analysis; Dexrazoxane; Female; Heart; Heart Failure; Humans; Male; Neoplasms
PubMed: 31531521
DOI: 10.1590/0102-311X00191518 -
Journal of Indian Association of... 2022Extravasation of chemotherapeutic agents from a peripheral cannula is a known problem, and to prevent that, oncology units use central vein access with indwelling...
Extravasation of chemotherapeutic agents from a peripheral cannula is a known problem, and to prevent that, oncology units use central vein access with indwelling catheters such as port-a-cath or Hickman catheter. The intrapleural extravasation of chemotherapeutic agents is a rare event. We describe a 9-year-old girl with newly diagnosed Ewing's sarcoma of the left upper humerus receiving neoadjuvant chemotherapy through a newly inserted port-a-cath device. The patient developed tachypnea and right-sided chest pain on day 2 of chemotherapy. The radiological investigations confirmed the extravasation of doxorubicin into the pleural space. The surgical washout with chest-drain insertion was done, and we continued flushing with normal saline until the drain fluid became clear. She has completed neoadjuvant therapy. This case report shines light into scenarios where extravasation of anthracycline into the pleural cavity or thorax can be managed conservatively and in settings where dexrazoxane is unavailable without causing much delay in restarting the chemotherapy.
PubMed: 36530827
DOI: 10.4103/jiaps.jiaps_253_21 -
Gastrointestinal Tumors Aug 2019We present a female patient, 13 years old, with diagnosis of hepatocellular carcinoma of fibrolamellar type, which was rapidly evolving. The fibrolamellar hepatocellular...
We present a female patient, 13 years old, with diagnosis of hepatocellular carcinoma of fibrolamellar type, which was rapidly evolving. The fibrolamellar hepatocellular carcinoma invaded more than 80% of the hepatic parenchyma without surgical possibility or liver transplantation. Measures applied corresponded to chemotherapy of 1 cycle of cisplatin 40 mg/s/5 days + vincristine 1.5 mg/m/day, 5-fluorouracil, doxorubicin, and dexrazoxane. The case presented aggressive evolution of hepatocellular carcinoma, which led to acute liver failure, with hyperammonemia, sepsis, pulmonary focus plus septic shock, grade III-IV encephalopathy, portal hypertension, and ascites with intra-abdominal hypertension. Death occurred due to multiple organ failure, which involved respiratory failure type KDIGO 1 and 2, acute liver failure, severe pneumonia, pericardial effusion, AKIN 2 acute kidney injury, carcinoma, and pulmonary metastasis. This type of ailment is infrequent in children and adolescents, and the first symptoms are crucial to achieve treatment possibilities.
PubMed: 31602376
DOI: 10.1159/000499581 -
Cells Sep 2020Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the...
GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells.
Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte's death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and epoxysuccinate (-ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and -ES either alone or in combination with DOX in H9C2 cells. A H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and -ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of -ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells.
Topics: Animals; Apoptosis; Breast Neoplasms; Cardiotoxicity; Cell Respiration; Cell Survival; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Myoblasts, Cardiac; Oxidative Stress; Rats; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 32992522
DOI: 10.3390/cells9102177 -
Toxicological Sciences : An Official... Mar 2024Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However,...
Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase IIβ has recently been identified as a plausible target of anthracyclines in cardiomyocytes. We examined the putative topoisomerase IIβ selective agent XK469 as a potential cardioprotective and designed several new analogs. In our experiments, XK469 inhibited both topoisomerase isoforms (α and β) and did not induce topoisomerase II covalent complexes in isolated cardiomyocytes and HL-60, but induced proteasomal degradation of topoisomerase II in these cell types. The cardioprotective potential of XK469 was studied on rat neonatal cardiomyocytes, where dexrazoxane (ICRF-187), the only clinically approved cardioprotective, was effective. Initially, XK469 prevented daunorubicin-induced toxicity and p53 phosphorylation in cardiomyocytes. However, it only partially prevented the phosphorylation of H2AX and did not affect DNA damage measured by Comet Assay. It also did not compromise the daunorubicin antiproliferative effect in HL-60 leukemic cells. When administered to rabbits to evaluate its cardioprotective potential in vivo, XK469 failed to prevent the daunorubicin-induced cardiac toxicity in either acute or chronic settings. In the following in vitro analysis, we found that prolonged and continuous exposure of rat neonatal cardiomyocytes to XK469 led to significant toxicity. In conclusion, this study provides important evidence on the effects of XK469 and its combination with daunorubicin in clinically relevant doses in cardiomyocytes. Despite its promising characteristics, long-term treatments and in vivo experiments have not confirmed its cardioprotective potential.
Topics: Rats; Animals; Rabbits; Topoisomerase II Inhibitors; Anthracyclines; Cardiotoxicity; Daunorubicin; Doxorubicin; Antibiotics, Antineoplastic; DNA Topoisomerases, Type II; DNA Damage; Quinoxalines
PubMed: 38290791
DOI: 10.1093/toxsci/kfae008 -
Advances in Pharmacological and... 2024The emergence of drug-resistant parasites impedes disease management and eradication efforts. Hence, a reinvigorated attempt to search for potent lead compounds in the...
BACKGROUND
The emergence of drug-resistant parasites impedes disease management and eradication efforts. Hence, a reinvigorated attempt to search for potent lead compounds in the mangroves is imperative.
AIM
This study evaluates antiplasmodial activity, antioxidant properties, and cytotoxicity of leaf alkaloidal extracts.
METHODS
The leaves were macerated with 70% ethanol to obtain a total crude extract. Dichloromethane and chloroform-isopropanol (3 : 1, v/v) were used to extract the crude alkaloids and quaternary alkaloids from the total crude. The antiplasmodial activities of the alkaloidal extracts were performed against 3D7 chloroquine-sensitive clone via the SYBR Green I fluorescence assay with artesunate serving as the reference drug. The alkaloidal extracts were further evaluated for antioxidant properties via the total antioxidant capacity (TAC), the total glutathione concentration (GSH), the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, and the ferric-reducing antioxidant power (FRAP) methods. The cytotoxic activity of the alkaloidal extracts was tested on erythrocytes using a 3-(4,5-dimethylthiazol-2-yl)-5-diphenyltetrazolium bromide-MTT assay with little modification. The phytocompounds in the alkaloidal extracts were identified via gas chromatography-mass spectrometry (GC-MS) techniques.
RESULTS
The total crude extract showed good antiplasmodial activity (IC = 11.890 g/mL). The crude and quaternary alkaloidal extracts demonstrated promising antiplasmodial effects with IC values of 6.217 and 6.285 g/mL, respectively. The total crude and alkaloidal extracts showed good antioxidant properties with negligible cytotoxicity on erythrocytes with good selectivity indices. The GC-MS spectral analysis of crude alkaloidal extracts gave indole and isoquinoline alkaloids and several other compounds. Dexrazoxane was found to be the main compound predicted, with an 86% peak area in the quaternary alkaloidal extract.
CONCLUSION
The crude and quaternary alkaloidal extracts exhibited antiplasmodial activities and ability to inhibit oxidative stress with negligible toxicity on erythrocytes. This may be good characteristics to avoid oxidative stress related to infection in the treatment of malaria.
PubMed: 38235482
DOI: 10.1155/2024/4541581