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1
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Younis NS. β-Caryophyllene Ameliorates Cyclophosphamide Induced Cardiac Injury: The Association of TLR4/NFκB and Nrf2/HO1/NQO1 Pathways. J Cardiovasc Dev Dis 2022; 9:jcdd9050133. [PMID: 35621844 PMCID: PMC9145742 DOI: 10.3390/jcdd9050133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/25/2022] [Accepted: 04/25/2022] [Indexed: 02/01/2023] Open
Abstract
Background: β-caryophyllene (BCP), a natural sesquiterpene, is extensively present in the essential oils of several plants. Cyclophosphamide (CYC) is an anticancer drug. However, its clinical usage is inadequate due to its cardiotoxicity. The aim of this study was to study the effects of BCP on cardiac injury induced by CYC exposure, and to identify the underlying mechanism of action. Methods: Five groups of Wistar rats were allocated. Group I (Normal), II (BCP), and III (CYC) acted as controls. Group IV, V (CYC + BCP) received BCP in two doses (100 and 200 mg/kg, orally, respectively) for 14 days after CYC challenge. CYC groups received 200 mg/kg, i.p. of the drug once on the first day of experiments. Results: CYC group displayed numerous ECG and histological irregularities and cardiac markers elevation. CYC induced lipid peroxidation and oxidative stress intensification, as well as inflammatory and apoptotic markers escalation. Treatment with BCP resulted in modified ECG traces and histological sections. BCP mitigated cardiac markers and lipid peroxidation whereas intensified antioxidant capacity. BCP activated Nrf2, with subsequent HO1 and NQO1 amplification. BCP diminished TLR4/NFκB pathway, which consequently lessened the inflammatory and apoptosis responses. Conclusion: BCP administration was associated with activated Nrf2/HO1/NQO1 and inhibited TLR4/NFκB pathways with subsequent enhanced anti-oxidative capacity and diminished inflammatory and apoptosis responses.
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Affiliation(s)
- Nancy S Younis
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
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2
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Dionísio F, Araújo AM, Duarte-Araújo M, Bastos MDL, Guedes de Pinho P, Carvalho F, Costa VM. Cardiotoxicity of cyclophosphamide's metabolites: an in vitro metabolomics approach in AC16 human cardiomyocytes. Arch Toxicol 2022; 96:653-671. [PMID: 35088106 DOI: 10.1007/s00204-021-03204-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 12/09/2021] [Indexed: 12/11/2022]
Abstract
Cyclophosphamide is a widely used anticancer and immunosuppressive prodrug that unfortunately causes severe adverse effects, including cardiotoxicity. Although the exact cardiotoxic mechanisms are not completely understood, a link between cyclophosphamide's pharmacologically active metabolites, namely 4-hydroxycyclophosphamide and acrolein, and the toxicity observed after the administration of high doses of the prodrug is likely. Therefore, the objective of this study is to shed light on the cardiotoxic mechanisms of cyclophosphamide and its main biotransformation products, through classic and metabolomics studies. Human cardiac proliferative and differentiated AC16 cells were exposed to several concentrations of the three compounds, determining their basic cytotoxic profile and preparing the next study, using subtoxic and toxic concentrations for morphological and biochemical studies. Finally, metabolomics studies were applied to cardiac cells exposed to subtoxic concentrations of the aforementioned compounds to determine early markers of damage. The cytotoxicity, morphological and biochemical assays showed that 4-hydroxycyclophosphamide and acrolein induced marked cardiotoxicity at µM concentrations (lower than 5 µM), being significantly lower than the ones observed for cyclophosphamide (higher than 2500 μM). Acrolein led to increased levels of ATP and total glutathione on proliferative cells at 25 µM, while no meaningful changes were observed in differentiated cells. Higher levels of carbohydrates and decreased levels of fatty acids and monoacylglycerols indicated a metabolic cardiac shift after exposure to cyclophosphamide's metabolites, as well as a compromise of precursor amino acids used in the synthesis of glutathione, seen in proliferative cells' metabolome. Overall, differences in cytotoxic mechanisms were observed for the two different cellular states used and for the three molecules, which should be taken into consideration in the study of cyclophosphamide cardiotoxic mechanisms.
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Affiliation(s)
- Flávio Dionísio
- UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Ana Margarida Araújo
- UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Margarida Duarte-Araújo
- LAQV/REQUIMTE, Department of Imuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Maria de Lourdes Bastos
- UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Paula Guedes de Pinho
- UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Félix Carvalho
- UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal.,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Vera Marisa Costa
- UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal. .,Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
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Chakraborty M, Bhattacharjee A, Kamath JV. Cardioprotective effect of curcumin and piperine combination against cyclophosphamide-induced cardiotoxicity. Indian J Pharmacol 2017; 49:65-70. [PMID: 28458425 PMCID: PMC5351241 DOI: 10.4103/0253-7613.201015] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE Curcumin is a well-established cardioprotective phytoconstituent, but the poor bioavailability associated with it is always a matter of therapeutic challenge. The present study was undertaken to increase the therapeutic efficacy of curcumin by combining with bio-enhancer like piperine against cyclophosphamide (CP)-induced cardiotoxicity in rats. MATERIALS AND METHODS Rats (n = 8) were treated with curcumin (200 mg/kg, p.o.) alone and different dose combination of curcumin (100, 50, 25 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 10 days. All the treated groups were subjected to CP (200 mg/kg, i.p.) toxicity on day 1. Twenty-four hours after the last treatment, the effects were evaluated by changes in electrocardiographic (ECG) parameters, serum biomarkers, lipid profile, tissue antioxidants, and histopathological examination. Serum and tissue homogenate parameters were measured by semi-autoanalyzer and spectrophotometer, respectively. Results obtained were assessed by one-way analysis of variance followed by Tukey-Karmer multiple comparison test. RESULTS Incorporation of piperine with the doses of 50 and 25 mg/kg with curcumin exhibited significant beneficial effect compared to curcumin alone-treated group. The best effective group was a combination of curcumin 50 mg/kg with piperine 20 mg/kg which showed extremely significant (P < 0.001) decrease and increase in ECG and serum biomarker level, respectively, and moderate significant (P < 0.01) decrease in lipid profile, antioxidant levels, and histopathological score, compared to curcumin alone-treated group. CONCLUSION From this study, it can be concluded that a novel dose combination of curcumin (50 mg/kg) with piperine (20 mg/kg) exhibited profound cardioprotection compared to curcumin (200 mg/kg) alone-treated group.
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Affiliation(s)
- Manodeep Chakraborty
- Department of Pharmacology, Shree Devi College of Pharmacy, Mangalore, Karnataka, India
| | - Ananya Bhattacharjee
- Department of Pharmacology, Shree Devi College of Pharmacy, Mangalore, Karnataka, India
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Hrynchak I, Sousa E, Pinto M, Costa VM. The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs. Drug Metab Rev 2017; 49:158-196. [DOI: 10.1080/03602532.2017.1316285] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Ivanna Hrynchak
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Emília Sousa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
- CIIMAR – Centro Interdisciplinar de Investigação Marinha e Ambiental, Matosinhos, Portugal
| | - Madalena Pinto
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
- CIIMAR – Centro Interdisciplinar de Investigação Marinha e Ambiental, Matosinhos, Portugal
| | - Vera Marisa Costa
- Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, UCIBIO, REQUIMTE (Rede de Química e Tecnologia), Universidade do Porto, Porto, Portugal
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Bhatt L, Sebastian B, Joshi V. Mangiferin protects rat myocardial tissue against cyclophosphamide induced cardiotoxicity. J Ayurveda Integr Med 2017; 8:62-67. [PMID: 28610894 PMCID: PMC5496998 DOI: 10.1016/j.jaim.2017.04.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 03/29/2017] [Accepted: 04/06/2017] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Mangiferin is a highly potent antioxidant present in mango leaves which is utilized for therapeutic purposes. OBJECTIVE The present study was undertaken to evaluate the cardioprotective effect of mangiferin against cyclophosphamide induced cardiotoxicity. MATERIALS AND METHODS Rats were treated with 100 mg/kg of mangiferin in alone and interactive groups for 10 days. Apart from normal and mangiferin control groups, all the groups were subjected to cyclophosphamide (200 mg/kg, i.p.) toxicity on Day 1 and effects of different treatments were analyzed by changes in serum biomarkers, tissue antioxidant levels, electrocardiographic parameters, lipid profile and histopathological evaluation. RESULTS Mangiferin treated group showed decrease in serum biomarker enzyme levels and increase in tissue antioxidant levels. Compared to cyclophosphamide control group, mangiferin treated animals showed improvement in lipid profile, electrocardiographic parameters, histological score and mortality. CONCLUSION The present findings clearly suggest the protective role of mangiferin as a powerful antioxidant preventing cardiotoxicity caused by cyclophosphamide.
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Affiliation(s)
- Laxit Bhatt
- Department of Pharmacology, Shree Devi College of Pharmacy, Airport Road, Kenjar Village, Malavoor Panchayat, Mangalore, 575412 Karnataka, India.
| | - Binu Sebastian
- Department of Pharmacology, Shree Devi College of Pharmacy, Airport Road, Kenjar Village, Malavoor Panchayat, Mangalore, 575412 Karnataka, India
| | - Viraj Joshi
- Department of Quality Assurance, Shree Devi College of Pharmacy, Airport Road, Kenjar Village, Malavoor Panchayat, Mangalore, 575412 Karnataka, India
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Sudharsan PT, Mythili Y, Selvakumar E, Varalakshmi P. Cardioprotective effect of pentacyclic triterpene, lupeol and its ester on cyclophosphamide-induced oxidative stress. Hum Exp Toxicol 2016; 24:313-8. [PMID: 16004198 DOI: 10.1191/0960327105ht530oa] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cyclophosphamide (CP), an alkylating agent widely used in cancer chemotherapy, causes fatal cardiotoxicity. In the present study, lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate were investigated for their possible cardioprotective effects against CP-induced toxicity. Male albino rats of Wistar strain were injected with a single dose of CP (200 mg/kg body weight, ip). In CP-administered rats, activities of lactate dehydrogenase and creatine phosphokinase were elevated in serum with a concomitant decline in their activities in the cardiac tissue. Significant increases (P B < 0.001) in the levels of lipid peroxides and a decrease (P B < 0.001) in the levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-s-transferase) and nonenzymic (reduced glutathione, vitamin C and vitamin E) antioxidants in the heart were also observed. The cardioprotective effects of lupeol (50 mg/kg body weight for 10 days orally) and its ester, lupeol linoleate (50 mg/kg body weight for 10 days orally) were evident from the significant reversal of the above alterations induced by CP. These observations highlight the antioxidant property of triterpenes and their cytoprotective action against CPinduced cardiotoxicity.
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Affiliation(s)
- P T Sudharsan
- Department of Medical Biochemistry, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, India
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Cheng WL, Kao YH, Chen SA, Chen YJ. Pathophysiology of cancer therapy-provoked atrial fibrillation. Int J Cardiol 2016; 219:186-94. [PMID: 27327505 DOI: 10.1016/j.ijcard.2016.06.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 06/11/2016] [Indexed: 02/07/2023]
Abstract
Atrial fibrillation (AF) occurs with increased frequency in cancer patients, especially in patients who undergo surgery or chemotherapy. AF disturbs the prognosis of cancer patients and challenges therapeutic outcomes of cancer treatment. Elucidating the mechanisms of cancer-induced AF would help identify specific strategies for preventing AF occurrence. In addition to concurrent risk factors of cancer and AF, cancer surgery, side effects of anticancer agents, and cancer-associated immune responses play critical roles in the genesis of AF. In this review, we provide succinct potential mechanisms of AF genesis in cancer patients.
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Affiliation(s)
- Wan-Li Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Shih-Ann Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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8
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Alhumaidha KA, Saleh DO, Abd El Fattah MA, El-Eraky WI, Moawad H. Cardiorenal protective effect of taurine against cyclophosphamide-induced toxicity in albino rats. Can J Physiol Pharmacol 2015; 94:131-139. [PMID: 26695545 DOI: 10.1139/cjpp-2015-0138] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cyclophosphamide (CP) is a cytotoxic alkylating agent used in the treatment of malignant diseases and autoimmune disorders. Its clinical use is limited to its marked cardiorenal toxicity. The present study aimed to investigate the possible protective role of taurine (Tau; 200 mg·kg-1 per day, i.p.) on CP-induced cardiorenal toxicity. CP (200 mg·kg-1) was administered as a single intraperitoneal injection whereas; Tau was administered for 3 weeks on a daily basis. The results showed that CP produced an elevation in serum activities of creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, creatinine as well as blood urea nitrogen. CP also induced an elevation in the oxidative stress markers viz. elevation in the serum lipid peroxides level (measured as malondialdehyde; MDA) and reduction in reduced glutathione level and superoxide dismutase activity in both heart and renal tissue. On the other hand, administration of Tau attenuated the CP-evoked disturbances in the above mentioned parameters. In addition, CP exhibited electrocardiographic (ECG) changes, which were significantly reversed by Tau treatment. Finally, the histopathological examination emphasized the obtained results. In conclusion, Tau is suggested to be a potential candidate to ameliorate CP-induced cardiorenal toxicity that may be related to its antioxidant activity.
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Affiliation(s)
- Khaled A Alhumaidha
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
| | - Dalia O Saleh
- b Pharmacology Department, National Research Centre, Cairo, Egypt
| | - Mai A Abd El Fattah
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
| | - Wafaa I El-Eraky
- b Pharmacology Department, National Research Centre, Cairo, Egypt
| | - Helmy Moawad
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
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Ezquer F, Gutiérrez J, Ezquer M, Caglevic C, Salgado HC, Calligaris SD. Mesenchymal stem cell therapy for doxorubicin cardiomyopathy: hopes and fears. Stem Cell Res Ther 2015; 6:116. [PMID: 26104315 PMCID: PMC4478637 DOI: 10.1186/s13287-015-0109-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy has made an essential contribution to cancer treatment in recent decades despite its adverse effects. As cancer survivors have increased, concern about ex-patient lifespan has become more important too. Doxorubicin is an effective anti-neoplastic drug that produces a cardiotoxic effect. Cancer survivors who received doxorubicin became more vulnerable to cardiac disease than the normal population did. Many efforts have been made to prevent cardiac toxicity in patients with cancer. However, current therapies cannot guarantee permanent cardiac protection. One of their main limitations is that they do not promote myocardium regeneration. In this review, we summarize and discuss the promising use of mesenchymal stem cells for cardio-protection or cardio-regeneration therapies and consider their regenerative potential without leaving aside their controversial effects on tumor progression.
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Affiliation(s)
- Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12348, Lo Barnechea, Santiago, 7690000, Chile
| | - Jaime Gutiérrez
- Facultad Ciencias de la Salud, Universidad San Sebastián, Lota 2465, 1° piso Edificio A, Providencia, Santiago, 7500000, Chile
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12348, Lo Barnechea, Santiago, 7690000, Chile
| | - Christian Caglevic
- Fundación Arturo Lopez Pérez, Rancagua, Providencia, Santiago, 7500000, Chile
| | - Helio C Salgado
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Sebastián D Calligaris
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Av. Las Condes 12348, Lo Barnechea, Santiago, 7690000, Chile.
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Chakraborty M, Kamath JV, Bhattacharjee A. Pharmacodynamic Interaction of Green Tea Extract with Hydrochlorothiazide against Cyclophosphamide-Induced Myocardial Damage. Toxicol Int 2014; 21:196-202. [PMID: 25253931 PMCID: PMC4170563 DOI: 10.4103/0971-6580.139810] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Objective: Treatment of ischemic hypertensive patients with hydrochlorothiazide can precipitate cardiac arrhythmias. Green tea by virtue of its antioxidant potential is responsible for cardio-protective activity. The present study was undertaken to evaluate the pharmacodynamic interaction of green tea extract with hydrochlorothiazide against cyclophosphamide-induced myocardial toxicity. Materials and Methods: Rats were treated with high (500 mg/kg, p.o.) and low (100 mg/kg, p.o.) dose of green tea extract in alone and interactive groups for 10 days. Standard, high, and low dose of interactive groups received hydrochlorothiazide (10 mg/kg, p.o.) for last 7 days. Apart from normal control, all other groups were subjected to cyclophosphamide (200 mg/kg, i.p.) toxicity on day first and the effects of different treatments were evaluated by changes in electrocardiographic parameters, serum biomarkers, and tissue antioxidant levels. Apart from that, lipid profile and histological studies were also carried out. Results: Compared to cyclophosphamide control group, both high and low dose of green tea exhibited significant decrease in serum biomarkers and increase in tissue antioxidant levels. Green tea treatment was also responsible for significant improvement in echocardiography (ECG) parameter, lipid profile, and histological score. Incorporation of high and low dose of green tea with hydrochlorothiazide-exhibited significant protection compared to hydrochlorothiazide-alone-treated group. Conclusion: The present findings clearly suggested that green tea extract dose dependently reduces cyclophosphamide-induced myocardial toxicity. Green tea when combined with hydrochlorothiazide can reduce the associated side effects and exhibits myocardial protection.
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Affiliation(s)
- Manodeep Chakraborty
- Research Scholar, Department of Pharmacology, Bhagwant University, Ajmer, Rajasthan, India
| | | | - Ananya Bhattacharjee
- Department of Pharmacology, Shree Devi College of Pharmacy, Mangalore, Karnataka, India
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Viswanatha Swamy AHM, Patel UM, Koti BC, Gadad PC, Patel NL, Thippeswamy AHM. Cardioprotective effect of Saraca indica against cyclophosphamide induced cardiotoxicity in rats: a biochemical, electrocardiographic and histopathological study. Indian J Pharmacol 2013; 45:44-8. [PMID: 23543849 PMCID: PMC3608294 DOI: 10.4103/0253-7613.106434] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 10/09/2012] [Accepted: 10/29/2012] [Indexed: 11/04/2022] Open
Abstract
Objectives: Cardioprotective activity of alcoholic extract of Saraca indica (SI) bark was investigated against cyclophosphamide induced cardiotoxicity. Materials and Methods: Cardiotoxicity was induced in Wistar rats by administering cyclophosphamide (200 mg/kg, i.p.) single injection on first day of experimental period. Saraca indica (200 and 400 mg/kg, p.o.) was administered immediately after administration of cyclophosphamide on first day and daily for 10 days. The general observations and mortality were measured. Results: Cyclophosphamide administration significantly (p < 0.05) increased lipid peroxidation (LPO) and decreased the levels of antioxidant markers such as reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Cyclophosphamide elevated the levels of biomarker enzymes like creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). Further, the cyclophosphamide treated rats showed changes in electrocardiogram (ECG) along with increased levels of cholesterol and triglycerides. Treatment with Saraca indica significantly (p < 0.05) reversed the status of cardiac biomarkers, ECG, oxidative enzymes and lipid profile in cyclophosphamide induced cardiotoxicity. Potential cardioprotective effect of Saraca indica was supported by histopathological examination that reduced severity of cellular damage of the myocardium. Conclusion: The biochemical, ECG and histopathology reports support the cardioprotective effect of Saraca indica which could be attributed to antioxidant activity.
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Affiliation(s)
- A H M Viswanatha Swamy
- Department of Pharmacology, KLE University's College of Pharmacy, Hubli - 580 031, India
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12
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Costa VM, Carvalho F, Duarte JA, Bastos MDL, Remião F. The Heart As a Target for Xenobiotic Toxicity: The Cardiac Susceptibility to Oxidative Stress. Chem Res Toxicol 2013; 26:1285-311. [PMID: 23902227 DOI: 10.1021/tx400130v] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Vera Marisa Costa
- REQUIMTE (Rede de Química e Tecnologia),
Laboratório de Toxicologia, Departamento de Ciências
Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Félix Carvalho
- REQUIMTE (Rede de Química e Tecnologia),
Laboratório de Toxicologia, Departamento de Ciências
Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | | | - Maria de Lourdes Bastos
- REQUIMTE (Rede de Química e Tecnologia),
Laboratório de Toxicologia, Departamento de Ciências
Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Fernando Remião
- REQUIMTE (Rede de Química e Tecnologia),
Laboratório de Toxicologia, Departamento de Ciências
Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
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Dhesi S, Chu MP, Blevins G, Paterson I, Larratt L, Oudit GY, Kim DH. Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management. J Investig Med High Impact Case Rep 2013; 1:2324709613480346. [PMID: 26425570 PMCID: PMC4528786 DOI: 10.1177/2324709613480346] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies.
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Affiliation(s)
| | | | | | - Ian Paterson
- University of Alberta, Edmonton, Alberta, Canada
| | | | | | - Daniel H Kim
- University of Alberta, Edmonton, Alberta, Canada
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Posser T, Franco JL, dos Santos DA, Rigon AP, Farina M, Dafré AL, Teixeira Rocha JB, Leal RB. Diphenyl diselenide confers neuroprotection against hydrogen peroxide toxicity in hippocampal slices. Brain Res 2008; 1199:138-47. [DOI: 10.1016/j.brainres.2008.01.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2007] [Revised: 12/28/2007] [Accepted: 01/03/2008] [Indexed: 01/05/2023]
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Senthilkumar S, Yogeeta SK, Subashini R, Devaki T. Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem Biol Interact 2006; 160:252-60. [PMID: 16554041 DOI: 10.1016/j.cbi.2006.02.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2005] [Revised: 02/02/2006] [Accepted: 02/13/2006] [Indexed: 11/19/2022]
Abstract
Cyclophosphamide (CP) is a widely used antineoplastic drug, which could cause toxicity of the normal cells due to its toxic metabolites. In this study, the protective role of squalene (SQ) towards the tissue defense system in the toxicity induced by CP (150 mg/kg b.w., twice, in 2 consecutive days) was studied in the experimental rats. The significant (P<0.05) alterations in the levels of enzymic [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR)] and non-enzymic antioxidants [total reduced glutathione (GSH), Vitamin E (Vit.E), Vitamin C (Vit.C) and ceruloplasmin] of the heart, red blood cell (RBC) hemolysate and plasma were investigated in the CP toxicity. Alterations in the levels of thiobarbutric acid reactive substance (TBARS) in heart, RBC hemolysate and plasma were also observed as a measure of lipid peroxidation (LPO). These pathological alterations due to CP administration were attenuated by the oral treatment of SQ at a dose of 0.4 ml/day/rat. These observations demonstrate the protective role of SQ towards the tissue defense system of the rats in the CP induced toxicity.
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Affiliation(s)
- Subramanian Senthilkumar
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India
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16
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Sivalokanathan S, Vijayababu MR, Balasubramanian MP. Effects of Terminalia arjuna bark extract on apoptosis of human hepatoma cell line HepG2. World J Gastroenterol 2006; 12:1018-24. [PMID: 16534840 PMCID: PMC4087891 DOI: 10.3748/wjg.v12.i7.1018] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of Terminalia arjuna (T. arjuna) extract on human hepatoma cell line (HepG2) and its possible role in induction of apoptosis.
METHODS: Human hepatoma cells were treated with different concentrations of ethanolic extract of T. arjuna and its cytotoxicity effect was measured by trypan blue exclusion method and lactate dehydrogenase leakage assay. Apoptosis was analyzed by light and fluorescence microscopic methods, and DNA fragmentation. The mechanism of apoptosis was studied with expression of p53 and caspase-3 proteins. Glutathione (GSH) content was also measured in HepG2 cells after T. arjuna treatment.
RESULTS: T. arjuna inhibited the proliferation of HepG2 cells in a concentration-dependent manner. Apoptotic morphology was observed in HepG2 cells treated with T. arjuna at the concentrations of 60 and 100 mg/L. DNA fragmentation, accumulation of p53 and cleavage of procaspase-3 protein were observed in HepG2 cells after the treatment with T. arjuna. The depletion of GSH was observed in HepG2 cells treated with T. arjuna.
CONCLUSION: T. arjuna induced cytotoxicity in HepG2 cells in vitro. Apoptosis of HepG2 cells may be due to the DNA damage and expression of apoptotic proteins. Depletion of GSH may be involved in the induction of apoptosis of HepG2 cells.
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Affiliation(s)
- Sarveswaran Sivalokanathan
- Department of Pharmacology and Environmental Toxicology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai-600 113, Tamil Nadu, India
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17
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Abstract
Cyclophosphamide is an extensively used anticancer and immunosuppressive agent. It is a prodrug undergoing a complicated process of metabolic activation and inactivation. Technical difficulties in the accurate determination of the cyclophosphamide metabolites have long hampered the assessment of the clinical pharmacology of this drug. As these techniques are becoming increasingly available, adequate description of the pharmacokinetics of cyclophosphamide and its metabolites has become possible. There is incomplete understanding on the role of cyclophosphamide metabolites in the efficacy and toxicity of cyclophosphamide therapy. However, relationships between toxicity (cardiotoxicity, veno-occlusive disease) and exposure to cyclophosphamide and its metabolites have been established. Variations in the balance between metabolic activation and inactivation of cyclophosphamide owing to autoinduction, dose escalation, drug-drug interactions and individual differences have been reported, suggesting possibilities for optimisation of cyclophosphamide therapy. Knowledge of the pharmacokinetics of cyclophosphamide, and possibly monitoring the pharmacokinetics of cyclophosphamide in individuals, may be useful for improving its therapeutic index.
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Affiliation(s)
- Milly E de Jonge
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
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18
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Mythili Y, Sudharsan PT, Selvakumar E, Varalakshmi P. Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury. Chem Biol Interact 2005; 151:13-9. [PMID: 15607758 DOI: 10.1016/j.cbi.2004.10.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2004] [Revised: 10/24/2004] [Accepted: 10/24/2004] [Indexed: 10/26/2022]
Abstract
Cyclophosphamide (CP), one of the most widely prescribed antineoplastic drugs could cause a lethal cardiotoxicity. The present study is aimed at evaluating the role of DL-alpha-lipoic acid (LA) in oxidative cardiac damage induced by CP. Adult male Wistar rats were divided into four treatment groups. Two groups received single intraperitoneal injection of CP (200 mg/kg BW) to induce cardiotoxicity, one of these groups received LA treatment (25 mg/kg BW for 10 days). A vehicle treated control group and a LA drug control were also included. Cardiotoxicity, evident from increased activities of serum creatine phosphokinase, lactate dehydrogenase, aspartate transaminase and alanine transaminase in CP administered rats, was reversed by LA treatment. CP administered rats showed abnormal levels of enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (glutathione, vitamin C and vitamin E) along with high malondialdehyde levels. However, normalized lipid peroxidation and antioxidant defenses were reported in the LA treated rats. These findings highlight the efficacy of LA as a cytoprotectant in CP induced cardiotoxicity.
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Affiliation(s)
- Y Mythili
- Department of Medical Biochemistry, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600113, India
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Kamezaki K, Fukuda T, Makino S, Harada M. Cyclophosphamide-induced cardiomyopathy in a patient with seminoma and a history of mediastinal irradiation. Intern Med 2005; 44:120-3. [PMID: 15750271 DOI: 10.2169/internalmedicine.44.120] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 17-year-old man with mediastinal seminoma was treated with chemotherapy and mediastinal irradiation therapy. Then he received high-dose chemotherapy containing cyclophosphamide (CY) followed by autologous peripheral blood stem cell transplantation. He suffered from CY-induced cardiomyopathy beginning six days after the administration of high-dose CY. The predictable factors associated with the onset of CY-induced cardiomyopathy are not precisely known. It is suggested that the history of mediastinal irradiation was responsible for the onset of cardiomyopathy.
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20
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Sipos EP, Witham TF, Ratan R, Burger PC, Baraban J, Li KW, Piantadosi S, Brem H. L-buthionine sulfoximine potentiates the antitumor effect of 4-hydroperoxycyclophosphamide when administered locally in a rat glioma model. Neurosurgery 2001; 48:392-400. [PMID: 11220384 DOI: 10.1097/00006123-200102000-00032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVE L-buthionine sulfoximine (BSO) inhibits glutathione synthesis and may modulate tumor resistance to some alkylating agents, but it has not been proven effective in the treatment of intracranial neoplasms. To evaluate this drug for the treatment of brain tumors, we studied the use of BSO for potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model. METHODS The survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, BSO, 4-HC, or both BSO and 4-HC. The efficacy of intracranial 4-HC treatment was assessed with and without serial systemic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO. RESULTS The median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO therapy did not improve survival time. In animals that were treated systemically, both liver and tumor glutathione levels were significantly lower than they were in control animals. In the locally treated animals, glutathione levels were reduced in the brain tumor but not in the liver. CONCLUSION These results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma model. In addition, because local delivery of BSO within the brain did not deplete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.
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Affiliation(s)
- E P Sipos
- Department of Neurological Surgery, Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland, USA
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21
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Sipos EP, Witham TF, Ratan R, Burger PC, Baraban J, Li KW, Piantadosi S, Brem H. l-Buthionine Sulfoximine Potentiates the Antitumor Effect of 4-Hydroperoxycyclophosphamide When Administered Locally in a Rat Glioma Model. Neurosurgery 2001. [DOI: 10.1227/00006123-200102000-00032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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22
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Hassan M, Ljungman P, Ringdén O, Hassan Z, Oberg G, Nilsson C, Békassy A, Bielenstein M, Abdel-Rehim M, Georén S, Astner L. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant 2000; 25:915-24. [PMID: 10800057 DOI: 10.1038/sj.bmt.1702377] [Citation(s) in RCA: 120] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Busulphan and cyclophosphamide (Bu/CP) are widely used in preparative regimens for bone marrow transplantation. Many studies have shown a wide variation in busulphan pharmacokinetics. Moreover, higher rates of liver toxicity were reported in Bu/CP protocols than in a total body irradiation (TBI)-containing regimen. In the present paper we investigated the effect of the time interval between the last dose of busulphan and the first dose of cyclophosphamide on the pharmacokinetics of CP and its cytotoxic metabolite 4-hydroperoxycyclophosphamide (4-OHCP). Thirty-six patients undergoing bone marrow transplantation (BMT) were included in the study. We also investigated the occurrence of veno-occlusive disease, mucositis and graft-versus-host disease. Ten patients conditioned with CP followed by TBI served as a control group (TBI). Twenty-six patients were conditioned with Bu/CP. The patients received Bu (1 mg/kg x 4 for 4 days), followed by CP (60 mg/kg for 2 days) administered as a 1-h infusion. Patients received their CP therapy either 7-15 h (group A, n = 12) or 24-50 h (group B, n = 14) after the last dose of Bu. None of the patients were given phenytoin or any other drug known to enhance CP metabolism. The administration of CP less than 24 h after the last dose of Bu resulted in: (1) a significantly (P = 0.003) lower clearance for cyclophosphamide was observed in group A (0.036 l/h/kg) compared to 0.055 and 0.055 l/h/kg, in the B and TBI groups, respectively; (2) significantly (P = 0.002) longer elimination half-life in group A (10.93 h) than in groups B and TBI (6.87 and 7.52 h, respectively); (3) significantly (P < 0.001) lower exposure to the cytotoxic metabolite (4-OHCP), expressed as the ratio AUC4-OHCP/AUCCP, in group A (0.0053) than that obtained in group B (0.013) and group TBI (0.012); (4) the patients in group A had a significantly (P < 0.05) higher incidence of VOD (seven of 12) than the other groups, B and TBI (2/14 and 1/10, respectively); and (5) mucositis was significantly higher in group A patients (8/12), being seen in only one patient in group B and none in the TBI group. The present study has shown that the interval between busulphan and cyclophosphamide administration can negatively affect the pharmacokinetics of cyclophosphamide and its cytotoxic metabolite. We conclude that the timing of CP administration must be considered in order to improve drug efficacy and reduce conditioning-related toxicity.
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Affiliation(s)
- M Hassan
- Division of Hematology, KFC Novum, Sweden
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23
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Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem 1998; 273:11313-20. [PMID: 9556624 DOI: 10.1074/jbc.273.18.11313] [Citation(s) in RCA: 283] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tumor necrosis factor-alpha (TNFalpha)-induced cell death involves a diverse array of mediators and regulators including proteases, reactive oxygen species, the sphingolipid ceramide, and Bcl-2. It is not known, however, if and how these components are connected. We have previously reported that GSH inhibits, in vitro, the neutral magnesium-dependent sphingomyelinase (N-SMase) from Molt-4 leukemia cells. In this study, GSH was found to reversibly inhibit the N-SMase from human mammary carcinoma MCF7 cells. Treatment of MCF7 cells with TNFalpha induced a marked decrease in the level of cellular GSH, which was accompanied by hydrolysis of sphingomyelin and generation of ceramide. Pretreatment of cells with GSH, GSH-methylester, or N-acetylcysteine, a precursor of GSH biosynthesis, inhibited the TNFalpha-induced sphingomyelin hydrolysis and ceramide generation as well as cell death. Furthermore, no significant changes in GSH levels were observed in MCF7 cells treated with either bacterial SMase or ceramide, and GSH did not protect cells from death induced by ceramide. Taken together, these results show that GSH depletion occurs upstream of activation of N-SMase in the TNFalpha signaling pathway. TNFalpha has been shown to activate at least two groups of caspases involved in the initiation and "execution" phases of apoptosis. Therefore, additional studies were conducted to determine the relationship of GSH and the death proteases. Evidence is provided to demonstrate that depletion of GSH is dependent on activity of interleukin-1beta-converting enzyme-like proteases but is upstream of the site of action of Bcl-2 and of the execution phase caspases. Taken together, these studies demonstrate a critical role for GSH in TNFalpha action and in connecting major components in the pathways leading to cell death.
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Affiliation(s)
- B Liu
- Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
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Liu B, Hannun YA. Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 1997; 272:16281-7. [PMID: 9195931 DOI: 10.1074/jbc.272.26.16281] [Citation(s) in RCA: 228] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Sphingomyelin hydrolysis through the activation of sphingomyelinases has become a potentially important signaling pathway with the product ceramide implicated in the regulation of cell growth, differentiation, apoptosis, and inflammatory responses. However, little is known about the regulation of sphingomyelinases. In this study, we show that the magnesium-dependent, neutral pH-optimum and membrane-associated sphingomyelinase (N-SMase) is inhibited, in a dose-dependent manner, by glutathione (GSH) at physiological concentrations with a greater than 95% inhibition observed at 5 mM GSH. The inhibitory effect of GSH was reproduced by gamma-glutamyl-cysteine, but not the cysteinyl-glycine fragment of GSH. The S-modified GSH analogs were as effective as GSH in inhibiting the N-SMase. On the other hand, neither dithiothreitol nor beta-mercaptoethanol had any effect on the N-SMase, suggesting that the sulfhydryl in GSH is not required for inhibition of N-SMase. GSH had no effect on the acid pH-optimum SMase, whereas dithiothreitol inhibited the acid SMase. These results suggest that in cells the N-SMase is inactive in the presence of physiological concentrations of GSH (1-20 mM). Finally, treatment of cultured Molt-4 cells with the GSH synthesis inhibitor, L-buthionine-(SR)-sulfoximine, resulted in a time-dependent depletion of GSH, accompanied by an increased hydrolysis of sphingomyelin and production of ceramide. Since GSH depletion is observed in a variety of cells in the process of cellular injury and apoptosis, these studies suggest that depletion of GSH may be an important mechanism in activation of N-SMase. This mechanism may therefore bring together the fields of oxidative stress and signaling through products of sphingomyelin hydrolysis.
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Affiliation(s)
- B Liu
- Departments of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
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Choi J, Liu RM, Forman HJ. Adaptation to oxidative stress: quinone-mediated protection of signaling in rat lung epithelial L2 cells. Biochem Pharmacol 1997; 53:987-93. [PMID: 9174112 DOI: 10.1016/s0006-2952(96)00867-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Cells can respond to a sublethal oxidative stress by up-regulating their intracellular glutathione (GSH) pool. Such increased GSH concentration is likely to be protective against further oxidative challenge, and, in fact, pre-exposure to low levels of oxidants confers increased cellular resistance to subsequent greater oxidative stress. Previously, we have shown that pretreatment of rat lung epithelial L2 cells with sublethal concentrations of tert-butylhydroquinone (TBHQ) increases intracellular GSH concentration in a concentration- and time-dependent manner. This increase resulted from up-regulation of both gamma-glutamyltranspeptidase (GGT) and gamma-glutamylcysteine synthetase (GCS). Therefore, we investigated whether such increased GSH concentration protected these cells against a subtle loss in function caused by a subsequent challenge with sublethal concentrations of tert-butyl hydroperoxide (tBOOH) (< or = 200 microM), mimicking a physiological oxidative stress. Activation of L2 cell purinoreceptors with 100 microM ADP caused an elevation of intracellular Ca2+. This response was suppressed by a brief pre-exposure to tBOOH. The inhibition, however, was alleviated dramatically by a 16-hr pretreatment with 50 microM TBHQ. The same TBHQ pretreatment also protected the cells from ATP-depletion induced by tBOOH. L-Buthionine S,R-sulfoximine (BSO), an irreversible inhibitor of GCS, prevented the increase in intracellular GSH and also completely removed the protection by TBHQ in maintaining the ATP level. Thus, pre-exposure to a sublethal level of TBHQ results in protection of cell functions from hydroperoxide toxicity. This protection appears to depend on alteration of the intracellular GSH pool, the modulation of which constitutes an adaptive response to oxidative stress.
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Affiliation(s)
- J Choi
- Department of Molecular Pharmacology and Toxicology, University of Southern California, School of Pharmacy, Los Angeles 90033, U.S.A
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