Carnitine Deficiency: A Causative Clue or a Sequel in Carboplatin Myelosuppression
DOI:
https://doi.org/10.6000/1929-2279.2014.03.04.7Keywords:
Carboplatin, Carnitine, Myelosuppression, Micronucleus Assay, TNF-α, ATP Mitochondrial membrane potential.Abstract
We have previously demonstrated that carnitine deficiency aggravated paracetamol-induced hepatopathy and carboplatin-induced nephropathy. As a continuum, we have addressed in the current study as to whether carboplatin-induced myelosuppression would be exacerbated by carnitine deficiency. Challenging male Wistar rats with a single dose of carboplatin (35 mg/kg, IP) induced bone marrow suppression manifested as anemia, leucopenia, thrombocytopenia as well as increased frequencies of the micronucleated bone marrow cells; MPCE and MNCE with notable reduction in the P/N ratio. The platinum drug also elevated serum TNF-a and reduced serum free and total carnitine levels. Besides, ATP levels in red and T cells were lowered. Likewise, the mitochondrial membrane potential in T lymphocytes was reduced following the use of the potentiometric dye; JC-1, and this was well correlated with cellular ATP production. Carnitine deficiency exacerbated carboplatin myelotoxicity as it exaggerated all biochemical, hematological and cytogenetic parameters. To address as to whether carnitine deficiency was a causative clue or merely a sequel of carboplatin myelotoxicity, L-carnitine was supplemented ahead of carboplatin challenege. Herein, L-carnitine mitigated all the biochemical, hematological and cytogenetic effects possibly via modulating the release of TNF-a, cellular ATP production and restoring the mitochondrial membrane potential. Irrespective of the mechanisms involved, the current results may afford the potential role for carnitine supplementation as add-on nutraceutical in carboplatin-based chemotherapy.
References
Tsubata Y, Okimoto T, Miura K, Karino F, Iwamoto S, Tada M, Honda T, Hamaguchi S, Ohe M, Sutani A, Kuraki T, Hamada A, Isobe T. Phase I Clinical and Pharmacokinetic Study of Bi-weekly Carboplatin/Paclitaxel Chemotherapy in Elderly Patients with Advanced Non-small Cell Lung Cancer. Anticancer Res 2013; 33(1): 261-266. http://www.ncbi.nlm.nih.gov/pubmed/23267154
Glaze S, Teitelbaum L, Chu P, Ghatage P, Nation J, Nelson G. Dose-dense Paclitaxel with Carboplatin for advanced ovarian cancer: a feasible treatment alternative. J Obstet Gynaecol Can 2013; 35(1): 61-67.
Fury MG, Sherman E, Ho A, Katabi N, Sima C, Kelly KW, Nwankwo O, Haque S, Pfister DG. A phase I study of temsirolimus plus carboplatin plus paclitaxel for patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Cancer Chemother Pharmacol 2012; 70(1): 121-128. http://dx.doi.org/10.1007/s00280-012-1894-y
Soffietti R, Nobile M, Ruda R, Borgognone M, Costanza A, Laguzzi E, Mutani R. Second-line treatment with carboplatin for recurrent or progressive oligodendroglial tumors after PCV (procarbazine, lomustine, and vincristine) chemotherapy: a phase II study. Cancer 2004; 100: 807-813. http://dx.doi.org/10.1002/cncr.20042
Weycker D, Malin J, Edelsberg J, Glass A, Gokhale M, Oster G. Cost of neutropenic complications of chemotherapy. Ann Oncol 2008; 19: 454-460. http://dx.doi.org/10.1093/annonc/mdm525
Su WC, Chang SL, Chen TY, Chen JS, Tsao CJ. Comparison of in vitro growth-inhibitory activity of carboplatin and cisplatin on leukemic cells and hematopoietic progenitors: the myelosuppressive activity of carboplatin may be greater than its antileukemic effect. Jpn J Clin Oncol 2000; 30: 562-567. http://dx.doi.org/10.1093/jjco/hyd137
Weijl NI, Elsendoorn TJ, Lentjes EG, Hopman GD, Wipkink-Bakker A, Zwinderman AH, Cleton FJ, Osanto S. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study. Eur J Cancer 2004; 40: 1713-1723 http://dx.doi.org/10.1016/j.ejca.2004.02.029
Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit--when supplementation is necessary? Curr Pharm Biotechnol 2003; 4: 211-219. http://dx.doi.org/10.2174/1389201033489829
Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004; 1033: 42-51. http://dx.doi.org/10.1196/annals.1320.004
Broderick TL. Hypocarnitinaemia induced by sodium pivalate in the rat is associated with left ventricular dysfunction and impaired energy metabolism. Drugs R D 2006; 7: 153–161 rugs R D 2006; 7: 153–161 http://dx.doi.org/10.2165/00126839-200607030-00002
Calò LA, Vertolli U, Davis PA, Savica V. L-carnitine in hemodialysis patients. Hemodial Int 2012; 16(3): 428-434. http://dx.doi.org/10.1111/j.1542-4758.2012.00679.x
Goa KL, Brogden RN. L-Carnitine. A preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic cardiac disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. Drugs 1987; 34: 1-24. http://dx.doi.org/10.2165/00003495-198734010-00001
Athanassakis I, Mouratidou M, Sakka P, Evangeliou A, Spilioti M, Vassiliadis S. L-carnitine modifies the humoral immune response in mice after in vitro or in vivo treatment. Int Immunopharmacol 2001; 1: 1813-1822. http://dx.doi.org/10.1016/S1567-5769(01)00105-9
Izgut-Uysal VN, Agac A, Derin N. Effect of carnitine on stress-induced lipid peroxidation in rat gastric mucosa. J Gastroenterol 2001; 36: 231-236. http://dx.doi.org/10.1007/s005350170108
Kitamura Y, Satoh K, Satoh T, Takita M, Matsuura A. Effect of L-carnitine on erythroid colony formation in mouse bone marrow cells. Nephrol Dial Transplant 2005; 20: 981–984 http://dx.doi.org/10.1093/ndt/gfh758
Trovato GM, Iannetti E, Murgo AM, Carpinteri G, Catalano D. Body composition and long-term levo-carnitine supplementation. Clin Ter 1998; 149: 209-214.
Arafa HM. Carnitine deficiency: a possible risk factor in paracetamol hepatotoxicity. Arch Toxicol 2009; 83: 139-150. http://dx.doi.org/10.1007/s00204-008-0330-x
Al Majed AA. Carnitine deficiency provokes cisplatin-induced hepatotoxicity in rats. Basic Clin. Pharmacol. Toxicol 2007; 100: 145-150. http://dx.doi.org/10.1111/j.1742-7843.2006.00024.x
Prieto JA, Andrade F, Aldámiz-Echevarría L, Sanjurjo P. Determination of free and total carnitine in plasma by an enzymatic reaction and spectrophotometric quantitation spectrophotometric determination of carnitine. Clin Biochem 2006; 39(10): 1022-1027. http://dx.doi.org/10.1016/j.clinbiochem.2006.06.005
Wolters G, Kuijpers LP, Kacaki J, Schuurs AH. Enzyme-linked immunosorbent assay for hepatitis B surface antigen. J Infect Dis 1977; 136: 311-317. 17. http://dx.doi.org/10.1093/infdis/136.Supplement_2.S311
Von Ledebur M, Schmid W. The micronucleus test. Methodological aspects. Mutat Res 1973; 19: 109-117. http://dx.doi.org/10.1016/0027-5107(73)90118-8
Adler ID, Kliesch U, van Hummelen P, Kirsch-Volders M. Mouse micronucleus tests with known and suspect spindle poisons: results from two laboratories. Mutagenesis 1991; 6: 47-53. http://dx.doi.org/10.1093/mutage/6.1.47
Mirikova N, Riordan HD, Kirby RK, Klykov A, Jackson A. Monitoring of ATP Levels in Red Blood Cells and T Cells of Healthy and Ill Subjects and the Effects of Age on Mitochondrial Potential. J Orthomolec Med 2004; 20(1): 50-58.
Cossarizza A, Baccarani-Contri M, Kalashnikova G, Franceschi C. A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem Biophys Res Commun 1993; 197(1): 40-45 http://dx.doi.org/10.1006/bbrc.1993.2438
Coulter PP. The public health nurse in the ANA. Am J Nurs 1953; 53: 1201-1202. http://dx.doi.org/10.1097/00000446-195310000-00017
Karpova GV, Fomina TI, Voronova OL, Abramova EV, Loskutova OP. Early and delayed effects of carboplatin on the blood system. Bull Exp Biol Med 2001; 132: 1065-1069. http://dx.doi.org/10.1023/A:1017964407835
Neuwelt EA, Pagel MA, Hasler BP, Deloughery TG, Muldoon L. Therapeutic Efficacy of Aortic Administration of N-Acetylcysteine as a Chemoprotectant against Bone Marrow Toxicity after Intracarotid Administration of Alkylators, with or without Glutathione Depletion in a Rat Model. Cancer Res 2001; 61: 7868–7874.
Ulich TR, Shin SS, del Castillo J: Haematologic effects of TNF. Res Immunol 1993; 144: 347-354. http://dx.doi.org/10.1016/S0923-2494(93)80079-E
Voog, E, Bienvenu J, Warzocha K, Moullet I, Dumontet C, Thieblemont C, Monneret G, Gutowski M, Coiffier B, Salles G. Factors That Predict Chemotherapy-Induced Myelosuppression in Lymphoma Patients: Role of the Tumor Necrosis Factor Ligand-Receptor System. J Clin Oncol 2000; 18: 325-331.
Arafa HM. Carnitine deficiency aggravates carboplatin nephropathy through deterioration of energy status, oxidant/anti-oxidant balance, and inflammatory endocoids. Toxicology 2008; 254: 51-60. http://dx.doi.org/10.1016/j.tox.2008.09.010
Jaureguy M, Choukroun G. Factors affecting the response to erythropoiesis-stimulating agents. Nephrol Ther 2006; 2: 274-282.
Calò LA, Davis PA, Semplicini A, Pessina AC. L-Carnitine and erythropoiesis: relationship with haeme oxygenase-1. Nephrol Dial Transplant 2005; 20(8): 1769-1770. http://dx.doi.org/10.1093/ndt/gfh934
Santoro A, Lioi MB, Monfregola J, Salzano S, Barbieri R, Ursini MV. L-Carnitine protects mammalian cells from chromosome aberrations but not from inhibition of cell proliferation induced by hydrogen peroxide. Mutat Res 2005; 587: 16-25. http://dx.doi.org/10.1016/j.mrgentox.2005.07.005
Garcia CL, Filippi S, Mosesso P, Calvani M, Nicolai R, Mosconi L, Palitti F. The protective effect of L-carnitine in peripheral blood human lymphocytes exposed to oxidative agents. Mutagenesis 2006; 21: 21-27. http://dx.doi.org/10.1093/mutage/gei065
Abd-Allah AR, Al Majed AA, Al Yahya AA, Fouda SI, Al Shabana OA. L-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC). Arch Toxicol 2005; 79: 406-413. http://dx.doi.org/10.1007/s00204-004-0643-3
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