Journal of Cancer Research and Clinical Oncology

, Volume 132, Issue 2, pp 121–128 | Cite as

Effects of doxorubicin-containing chemotherapy and a combination with l-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma

  • Raimund Waldner
  • Claudia Laschan
  • Alfred Lohninger
  • Martin Gessner
  • Heinz Tüchler
  • Marlies Huemer
  • Wolfgang Spiegel
  • Heidrun Karlic
Original Paper

Abstract

Purpose: Chemotherapy regimens based on anthracycline (doxorubicin) are well established in lymphoma therapy. The purpose of this study was to examine the effects of l-carnitine with a view to reducing cytotoxic side-effects. Methods: 20 patients were scheduled to receive 3 g l-carnitine before each chemotherapy cycle, followed by 1 g l-carnitine/day during the following 21 days, while 20 patients received a placebo (randomized controlled trial). The plasma lipid profile and relative mRNA levels of key enzymes of oxidative metabolism (carnitine acyltransferases) were measured at three points of time. In addition to the clinical parameters we used the mRNA of white blood cells to evaluate the toxic effects on cardiomyocytes. Results: In the present study no cardiotoxicity of anthracycline therapy was detected. Carnitine treated patients showed a rise in plasma carnitine which led to an increase of relative mRNA levels from CPT1A (liver isoform of carnitine palmitoyltransferase) and OCTN2 (carnitine transporter). Following chemotherapy, an activation of carnitine acyltransferases was associated with a stimulation of OCTN2 in both groups. Conclusion: Biochemical and molecular analyses indicated a stimulation of oxidative metabolism in white blood cells through carnitine uptake.

Keywords

Anthracycline l-Carnitine Oxidative metabolism 

References

  1. Abd-Allah AR, Al-Majed AA, Al-Yahya AA, Fouda SI, Al-Shabana OA (2005) l-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC). Arch Toxicol 79:406–413CrossRefPubMedGoogle Scholar
  2. Abdel-aleem S, el-Merzabani MM, Sayed-Ahmed M, Taylor DA, Lowe JE (1997) Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes. J Mol Cell Cardiol 29:789–797CrossRefPubMedGoogle Scholar
  3. Al-Majed AA, Gdo AM, Al-Shabanah OA, Mansour MA (2002) Alpha-lipoic acid ameliorates myocardial toxicity induced by doxorubicin. Pharmacol Res 46:499–503CrossRefPubMedGoogle Scholar
  4. Anderlini P, Benjamin RS, Wong FC, Kantarjian HM, Andreeff M, Kornblau SM, O'Brien S, Mackay B, Ewer MS, Pierce SA (1995) Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myclodysplasia. J Clin Oncol 11:2827–2834Google Scholar
  5. Andrieu-Abadie N, Jaffrezou JP, Hatem S, Laurent G, Levade T, Mercaider JJ (1999) l-Carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: role of inhibition of ceramide generation. FASEB J 13:1501–1510PubMedGoogle Scholar
  6. Brown HR, Ni H, Benavides G, Yoon L, Hyder K, Giridhar J, Gardner G, Tyler RD, Morgan KT (2002) Correlation of simultaneous differential gene expression in the blood and heart with known mechanisms of adriamycin-induced cardiomyopathy in the rat. Toxicol Pathol 30:452–469CrossRefPubMedGoogle Scholar
  7. Choi KM, Lee J, Kim YH, Kim KB, Kim DL, Kim SG, Shin DH, Kim NH, Park IB, Choi DS, Baik SH (2003) Relation between insulin resistance and hematological parameters in elderly Koreans-Southwest Seoul (SWS) Study. Diabetes Res Clin Pract 60:205–212CrossRefPubMedGoogle Scholar
  8. Cruciani RA, Dvorkin E, Homel P, Culliney B, Malamud S, Shaiova L, Fleishman S, Lapin J, Klein E, Lesage P, Portenoy R, Esteban-Cruciani N (2004) l-Carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: a preliminary analysis. Ann NY Acad Sci 1033:168–176CrossRefPubMedGoogle Scholar
  9. Ganapathy ME, Huang W, Rajan DP, Carter AL, Sugawara M, Iseki K, Leibach FH, Ganapathy V (2000) Beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J Biol Chem 275:1699–1707CrossRefPubMedGoogle Scholar
  10. Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandez-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem 272:11369–11377CrossRefPubMedGoogle Scholar
  11. Gardner JP, Li S, Srinivasan SR, Chen W, Kimura M, Lu X, Berenson GS, Aviv A (2005) Rise in insulin resistance is associated with escalated telomere attrition. Circulation 111:2171–2177CrossRefPubMedGoogle Scholar
  12. Grynberg A (2005) Effectors of fatty acid oxidation reduction: promising new anti-ischaemic agents. Curr Pharm Des 11:489–509PubMedCrossRefGoogle Scholar
  13. Gurlek A, Tutar E, Akcil E, Dincer I, Erol C, Kocaturk PA, Oral D (2000) The effects of l-carnitine treatment on left ventricular function and erythrocyte superoxide dismutase activity in patients with ischemic cardiomyopathy. Eur J Heart Fail 2:189–193CrossRefPubMedGoogle Scholar
  14. Hale JP, Lewis IJ (1994) Anthracyclines: cardiotoxicity and its prevention. Arch Dis Child 71:457–462PubMedCrossRefGoogle Scholar
  15. Haripriya D, Sangeetha P, Kanchana A, Balu M, Panneerselvam C (2005) Modulation of age-associated oxidative DNA damage in rat brain cerebral cortex, striatum and hippocampus by l-carnitine. Exp Gerontol 40:129–135CrossRefPubMedGoogle Scholar
  16. Hofmann S, Tuchler H, Bernhart M, Stacher A, Lutz D (1993) A questionnaire suitable for general practice for detection of the health status and quality of life of patients with hemato-oncologic diseases: psychometric properties. The Study G “Quality of Life” of the International Society for Chemo- and Immunotherapy (I.G.C.I.). Wien Klin Wochenschr 105:277–283PubMedGoogle Scholar
  17. Karlic H, Lohninger S, Koeck T, Lohninger A (2002) Dietary l-carnitine stimulates carnitine acyltransferases in the liver of aged rats. J Histochem Cytochem 50:205–212PubMedGoogle Scholar
  18. Karlic H, Lohninger A, Laschan C, Lapin A, Bohmer F, Huemer M, Guthann E, Rappold E, Pfeilstocker M (2003) Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes. J Mol Med 81:435–442CrossRefPubMedGoogle Scholar
  19. Karlic H, Lohninger A (2004) Supplementation of L-carnitine in athletes: does it make sense? Nutrition 20:709–715CrossRefPubMedGoogle Scholar
  20. Kolovou GD, Anagnostopoulou KK, Cokkinos DV (2005) Pathophysiology of dyslipidaemia in the metabolic syndrome. Postgrad Med J 81:358–366CrossRefPubMedGoogle Scholar
  21. Kraemer WJ, Volek JS, French DN, Rubin MR, Sharman MJ, Gomez AL, Ratamess NA, Newton RU, Jemiolo B, Craig BW, Hakkinen K (2003) The effects of l-carnitine l-tartrate supplementation on hormonal responses to resistance exercise and recovery. J Strength Cond Res 17:455–462CrossRefPubMedGoogle Scholar
  22. Kumaran S, Savitha S, Anusuya Devi M, Panneerselvam C (2004) l-carnitine and dl-alpha-lipoic acid reverse the age-related deficit in glutathione redox state in skeletal muscle and heart tissues. Mech Ageing Dev 125:507–512CrossRefPubMedGoogle Scholar
  23. Kumaran S, Subathra M, Balu M, Panneerselvam C (2005) Supplementation of l-carnitine improves mitochondrial enzymes in heart and skeletal muscle of aged rats. Exp Aging Res 31:55–67CrossRefPubMedGoogle Scholar
  24. Lamhonwah AM, Skaug J, Scherer SW, Tein I (2003) A third human carnitine/organic cation transporter (OCTN3) as a candidate for the 5q31 Crohn’s disease locus (IBD5). Biochem Biophys Res Commun 301:98–101CrossRefPubMedGoogle Scholar
  25. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32:302–314PubMedCrossRefGoogle Scholar
  26. Lohninger A, Preis P, Linhart L, Sommoggy SV, Landau M, Kaiser E (1990) Determination of plasma free fatty acids, free cholesterol, cholesteryl esters, and triacylglycerols directly from total lipid extract by capillary gas chromatography. Anal Biochem 186:243–250CrossRefPubMedGoogle Scholar
  27. Lohninger A, Hofbauer R, Nissel H, Karlic H (2002) Carnitine and transcription of carnitine palmitoyltransferases—in vitro and in vivo studies. In: Richter RW, Rassoul F, Thiery J (eds) Lipoproteinmetabolismus und Atherosklerosepraevention. Wissenschaftliche Skripten, Leipzig, pp 113–122Google Scholar
  28. McFalls EO, Paulson DJ, Gilbert EF, Shug AL (1986) Carnitine protection against adriamycin-induced cardiomyopathy in rats. Life Sci 38:497–505CrossRefPubMedGoogle Scholar
  29. Mingrone G, Greco AV, Capristo E, Benedetti G, Giancaterini A, De Gaetano A, Gasbarrini G (1999) l-Carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr 18:77–82PubMedGoogle Scholar
  30. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229CrossRefPubMedGoogle Scholar
  31. Mutomba MC, Yuan H, Konyavko M, Adachi S, Yokoyama CB, Esser V, McGarry JD, Babior BM, Gottlieb RA (2000) Regulation of the activity of caspases by l-carnitine and palmitoylcarnitine. FEBS Lett 478:19–25CrossRefPubMedGoogle Scholar
  32. Nakamura T, Ueda Y, Juan Y, Katsuda S, Takahashi H, Koh E (2000) Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: in vivo study. Circulation 102:572–578PubMedGoogle Scholar
  33. Nakashima H, Ozono R, Suyama C, Sueda T, Kambe M, Oshima T (2004) Telomere attrition in white blood cell correlating with cardiovascular damage. Hypertens Res 27:319–325CrossRefPubMedGoogle Scholar
  34. Olson RD, Mushlin PS (1990) Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4:3076–3086PubMedGoogle Scholar
  35. Paterna S, Furitano G, Scaffidi L, Barbarino C, Campisi D, Parisi G, Carreca I (1984) Effects of l-carnitine on adriamycin-induced cardiomyopathy in rabbit. Int J Tissue React 6:91–95PubMedGoogle Scholar
  36. Paumen MB, Ishida Y, Han H, Muramatsu M, Eguchi Y, Tsujimoto Y, Honjo T (1997a) Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with Bcl-2. Biochem Biophys Res Commun 231:523–525CrossRefGoogle Scholar
  37. Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T (1997b) Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem 272:3324–3329CrossRefGoogle Scholar
  38. Peluso G, Nicolai R, Reda E, Benatti P, Barbarisi A, Calvani M (2000) Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system. J Cell Physiol 182:339–350CrossRefPubMedGoogle Scholar
  39. Pittner F, Lohninger A, Pittner G (2005) 100 Years research on carnitine. Chem Mon 136:1255–1544CrossRefGoogle Scholar
  40. Quiles JL, Huertas JR, Battino M, Mataix J, Ramirez-Tortosa MC (2002) Antioxidant nutrients and adriamycin toxicity. Toxicology 180:79–95CrossRefPubMedGoogle Scholar
  41. Quillet-Mary A, Jaffrezou JP, Mansat V, Bordier C, Naval J, Laurent G (1997) Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis. J Biol Chem 272:21388–21395CrossRefPubMedGoogle Scholar
  42. Rabbani A, Finn RM, Ausio J (2005) The anthracycline antibiotics: antitumor drugs that alter chromatin structure. Bioessays 27:50–56CrossRefPubMedGoogle Scholar
  43. Ramsay RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546:21–43PubMedGoogle Scholar
  44. Sayed-Ahmed MM, Shouman SA, Rezk BM, Khalifa MH, Osman AM, El-Merzabani MM (2000) Propionyl-l-carnitine as potential protective agent against adriamycin-induced impairment of fatty acid beta-oxidation in isolated heart mitochondria. Pharmacol Res 41:143–150CrossRefPubMedGoogle Scholar
  45. Singal PK, Iliskovic N, Li T, Kumar D (1997) Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J 11:931–936PubMedGoogle Scholar
  46. Tuchler H, Hofmann S, Bernhart M, Brugiatelli M, Chrobak L, Franke A, Herold M, Holowiecki J, Ihle R, Jaksic B et al (1992) A short multilingual quality of life questionnaire—practicability, reliability and interlingual homogeneity. Qual Life Res 1:107–117CrossRefPubMedGoogle Scholar
  47. Wagner CA, Lukewille U, Kaltenbach S, Moschen I, Broer A, Risler T, Broer S, Lang F (2000) Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2. Am J Physiol Renal Physiol 279:F584–F591PubMedGoogle Scholar
  48. Xuan W, Lamhonwah AM, Librach C, Jarvi K, Tein I (2003) Characterization of organic cation/carnitine transporter family in human sperm. Biochem Biophys Res Commun 306:121–128CrossRefPubMedGoogle Scholar
  49. Yoon HR, Hong YM, Boriack RL, Bennett MJ (2003) Effect of l-carnitine supplementation on cardiac carnitine palmitoyltransferase activities and plasma carnitine concentrations in adriamycin-treated rats. Pediatr Res 53:788–792CrossRefPubMedGoogle Scholar
  50. Zeibig J, Karlic H, Lohninger A, Dumsgaard R, Smekal G (2005) Do blood cells mimic gene expression profile alterations known to occur in muscular adaptation to endurance training ? Eur J Appl Physiol 7 April 2005 [Epub ahead of print] Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Raimund Waldner
    • 1
  • Claudia Laschan
    • 1
  • Alfred Lohninger
    • 3
  • Martin Gessner
    • 2
  • Heinz Tüchler
    • 6
  • Marlies Huemer
    • 4
  • Wolfgang Spiegel
    • 5
  • Heidrun Karlic
    • 6
  1. 1.3rd Department of MedicineHanusch HospitalViennaAustria
  2. 2.2nd Department of MedicineHanusch HospitalViennaAustria
  3. 3.Department of Medical ChemistryMedical University of Vienna ViennaAustria
  4. 4.Ludwig Boltzmann Institute for OsteologyHanusch HospitalViennaAustria
  5. 5.Department of General Practice, Center of Public HealthMedical University of ViennaViennaAustria
  6. 6.Ludwig Boltzmann Institute for Leukemia Research and HematologyHanusch HospitalViennaAustria

Personalised recommendations