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Year 2013, Volume: 35 Issue: 2, 166 - 171, 30.01.2013

Hülya Tosun Yıldırım , Gülden Diniz , Safiye Aktaş , Nur Olgun

Abstract

Aim. Doxorubicin is a widely used anticancer agent which can cause an unpredictable cardiac toxicity increases with its cumulative dose. Previous studies demonstrated that side effects of doxorubicin can be reduced by L-carnitine. However in only a few studies, toxic effects of doxorubicin on skeletal muscles was investigated widely. The objective of present study was to investigate the effects of doxorubicin and Acetyl L-carnitine on skeletal muscles in rats. Method. The study was performed on adult male Wistar-Albino rats which are 200-300 gr in weight. Rats were divided to four groups as control, doxorubicine, ALCAR and ALCAR + doxorubicine. The first group (n=7) was the control. The second and forth groups (n=6/n=6) received intraperitoneal doxorubicine (cumulative dose 15 mg/kg). Third and forth groups (n=7/n=6) received intraperitoneal ALCAR (300 mg/kg/day) and it was continued 10 days. All animals in each group were sacrificed on tenth day of the study and muscle biopsy samples were taken from quadriceps muscles. All samples were frozen and 8-micron sections were cut using cryostat. Slides were stained with routine hematoxylin eosin, enzyme histochemically combined COX and SDH, histochemically with modified Gomori’s trichrome, PAS and oil red O. Fast myosin antibody was used for discriminating myofiber type. Results. No significant differences were found in muscle fiber type distribution, lipid and glucogen accumulation, or mitocondrial function in Doxorubicine or ALCAR groups compared with control group. Conclusion. This study indicated that treatment with doxorubicine or ALCAR cannot produce significant injury to non-cardiac striated muscle tissue.

Keywords

Doxorubicin ALCAR skeletal muscle rat

References

  • Singal PK, Li T, Kumar D, Danelisen I, Iliskovic N. Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 2000; 207: 77-86.
  • Kaldır HT, Tatlı E, Turgut B, Vural Ö. Doxorubicin induced cardiotoxicity. Türkiye Klinikleri J Cardiol 2002; 15: 416-21.
  • Yavaşoğlu İ, Kadıköylü G, Bolaman Z. Antrasiklinler ve Bradikardi. Türkiye Klinikleri J Cardiovasc Sci 2008; 20: 30-1.
  • Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity. Pharmacol Rev 2004; 56: 185-229.
  • Müller I, Niethammer D, Bruchelt G. Anthracycline-derived chemotherapeutics in apoptosis and free radical cytotoxicity (Review).Int J Mol Med 1998; 1: 491-4. Cutts SM, Nudelman A, Rephaeli A, Phillips DR. The Power and Potential of Doxorubicin-DNA Adducts. IUBMB Life 2005; 57: 73-81.
  • Mordente A, Meucci E, Martorana GE, Giardina B, Minotti G. Human Heart Cytosolic Reductases and Anthracycline Cardiotoxicity. IUBMB Life 2001; 52: 83Menna P, Salvatorelli E, Minotti G. Cardiotoxicity of Antitumor Drugs. Chem Res Toxicol 2008; 21: 978-89.
  • Hale JP, Lewis IJ. Anthracyclines: cardiotoxicity and its prevention. Arch Dis Child 1994; 71: 457-62.
  • Monograph. L-carnitine. Altern Med Rev 2005; 10: 42-50.
  • Chao HH, Liu JC, Hong HJ, Lin JW, Chen CH, Cheng TH. L-Carnitine reduces doxorubicin-induced apoptosis through a prostacyclin-mediated pathway in neonatal rat cardiomyocytes. Int J Cardiol 2011; 146: 145-52.
  • Acetyl-L-Carnitine. Altern Med Rev 1999; 4: 438-41.
  • Calabrese V, Giuffrida Stella AM, Calvani M, Butterfield DA.Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes. J Nutr Biochem 2006; 17: 73-88.
  • Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol 2011; 110: 935-42.
  • Doroshow JH, Tallent C, Schechter JE. Ultrastructural Features of AdriamycinInduced Skeletal and Cardiac Muscle Toxicity. Am J Pathol 1985; 118: 288-97.
  • Çullu E, Özkan I, Çulhacı N, Alparslan B, Dikicioğlu E, Şavk SÖ. Doksorubisinin sıçan iskelet kasında kemomiyektomi etkisi. Acta Orthop Traumatol Turc 2003; 37: 323-9.
  • Deng S, Wojnowski L. Genotyping the risk of anthracycline-induced cardiotoxicity. Cardiovasc Toxicol 2007; 7: 129-34.
  • Berthiaume JM, Wallace KB. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 2007; 23: 15-25.
  • Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review. Health Technol Assess 2007; 11: iii, ix-x.
  • Bast A, Haenen GR, Bruynzeel AM, Van der Vijgh WJ. Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials. Cardiovasc Toxicol 2007; 7: 154-9.
  • Kaiserová H, Simunek T, Sterba M, den Hartog GJ, Schröterová L, Popelová O, Gersl V, Kvasnicková E, Bast A. New iron chelators in anthracycline-induced cardiotoxicity. Cardiovasc Toxicol 2007; 7: 145-50.
  • Zeidán Q, Strauss M, Porras N, Anselmi G. Differential long-term subcellular responses in heart and liver to adriamycin stress. Exogenous L-carnitine cardiac and hepatic protection. J Submicrosc Cytol Pathol 2002; 34; 315-21.
  • Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep 1978; 62: 955-61.
  • Hirano S, Wakazono K, Agata N, Iguchi H, Tone H. Comparison of cardiotoxicity of pirarubicin, epirubicin and doxorubicin in the rat. Drugs Exp Clin Res 1994; 20: 153-60.

Asetil L-karnitin ve doksorubisinin rat çizgili kası üzerine etkilerinin araştırılması

Year 2013, Volume: 35 Issue: 2, 166 - 171, 30.01.2013

Hülya Tosun Yıldırım , Gülden Diniz , Safiye Aktaş , Nur Olgun

Abstract

Özet

Amaç. Doksorubisin, ilacın birikmiş dozuna bağlı olarak öngörülemeyen kardiotoksisiteye yol açan, yaygın olarak kullanılan bir kanser ilacıdır. Önceki çalışmalar doxorubicinin bu yan etkisinin L-karnitin ile azaldığını göstermiştir. Ancak sadece az sayıda çalışmada doksorubisinin iskelet kası üzerine toksik etkisi ayrıntılı olarak irdelenmiştir. Bu çalışmanın amacı, doksorubisin ve asetil L-karnitinin sıçan çizgili kasındaki etkilerinin araştırılmasıdır. Yöntem. Çalışma, ağırlıkları 200-300 g arasında değişen erişkin erkek Wistar- Albino şıçanlar üzerinde gerçekleştirildi. Sıçanlar kontrol, doksorubisin, ALKAR ve doksorubisin + ALKAR olmak üzere 4 gruba ayrıldı. İlk grup (n=7) kontrol grubuydu. İkinci ve dördüncü gruba (n=6/ n=6) intraperitoneal doksorubusin verildi (kümülatif doz 15mg/kg). Üçüncü ve dördüncü gruba (n=7/ n=6) 10 gün süreyle intraperitoneal ALKAR verildi (300 mg/kg/gün). Tüm hayvanlar çalışmanın 10. günü sakrifiye edildi ve kuadriseps kasından kas biyopsi örnekleri alındı. Tüm örnekler donduruldu ve kriyostatla 8- mikronluk kesitler yapıldı. Tüm preparatlar rutin hematoksilen eozin boyasıyla, kombine COX- SDH enzim boyalarıyla ve histokimyasal modifiye Gomori trikrom, PAS ve oil red O boyalarıyla boyandı. Myofiber tip ayrımı için fast myozin antikoru kullanıldı. Bulgular. Kontrol grubuyla karşılaştırıldığında, kas fiber tip dağılımı, lipit ve glikojen depolanması ile mitokondrial fonksiyonlar açısından doksorubisin veya ALKAR grubunda anlamlı fark bulunmadı. Tartışma. Bu çalışma doksorubisin veya ALKAR tedavisinin kalp-dışı çizgili kas dokusunda önemli incinmeye etken olmadığını göstermiştir.

Anahtar sözcükler: Doksorubisin, ALKAR, iskelet kası, sıçan

 

Abstract

Aim. Doxorubicin is a widely used anticancer agent which can cause an unpredictable cardiac toxicity increases with its cumulative dose. Previous studies demonstrated that side effects of doxorubicin can be reduced by L-carnitine. However in only a few studies, toxic effects of doxorubicin on skeletal muscles was investigated widely. The objective of present study was to investigate the effects of doxorubicin and Acetyl L-carnitine on skeletal muscles in rats. Method. The study was performed on adult male Wistar-Albino rats which are 200-300 gr in weight. Rats were divided to four groups as control, doxorubicine, ALCAR and ALCAR + doxorubicine. The first group (n=7) was the control. The second and forth groups (n=6/n=6) received intraperitoneal doxorubicine (cumulative dose 15 mg/kg). Third and forth groups (n=7/n=6) received intraperitoneal ALCAR (300 mg/kg/day) and it was continued 10 days. All animals in each group were sacrificed on tenth day of the study and muscle biopsy samples were taken from quadriceps muscles. All samples were frozen and 8-micron sections were cut using cryostat. Slides were stained with routine hematoxylin eosin, enzyme histochemically combined COX and SDH, histochemically with modified Gomori’s trichrome, PAS and oil red O. Fast myosin antibody was used for discriminating myofiber type. Results. No significant differences were found in muscle fiber type distribution, lipid and glucogen accumulation, or mitocondrial function in Doxorubicine or ALCAR groups compared with control group. Conclusion. This study indicated that treatment with doxorubicine or ALCAR cannot produce significant injury to non-cardiac striated muscle tissue.

Keywords: Doxorubicin, ALCAR, skeletal muscle, rat

Keywords

Doksorubisin ALKAR iskelet kası sıçan

References

  • Singal PK, Li T, Kumar D, Danelisen I, Iliskovic N. Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 2000; 207: 77-86.
  • Kaldır HT, Tatlı E, Turgut B, Vural Ö. Doxorubicin induced cardiotoxicity. Türkiye Klinikleri J Cardiol 2002; 15: 416-21.
  • Yavaşoğlu İ, Kadıköylü G, Bolaman Z. Antrasiklinler ve Bradikardi. Türkiye Klinikleri J Cardiovasc Sci 2008; 20: 30-1.
  • Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity. Pharmacol Rev 2004; 56: 185-229.
  • Müller I, Niethammer D, Bruchelt G. Anthracycline-derived chemotherapeutics in apoptosis and free radical cytotoxicity (Review).Int J Mol Med 1998; 1: 491-4. Cutts SM, Nudelman A, Rephaeli A, Phillips DR. The Power and Potential of Doxorubicin-DNA Adducts. IUBMB Life 2005; 57: 73-81.
  • Mordente A, Meucci E, Martorana GE, Giardina B, Minotti G. Human Heart Cytosolic Reductases and Anthracycline Cardiotoxicity. IUBMB Life 2001; 52: 83Menna P, Salvatorelli E, Minotti G. Cardiotoxicity of Antitumor Drugs. Chem Res Toxicol 2008; 21: 978-89.
  • Hale JP, Lewis IJ. Anthracyclines: cardiotoxicity and its prevention. Arch Dis Child 1994; 71: 457-62.
  • Monograph. L-carnitine. Altern Med Rev 2005; 10: 42-50.
  • Chao HH, Liu JC, Hong HJ, Lin JW, Chen CH, Cheng TH. L-Carnitine reduces doxorubicin-induced apoptosis through a prostacyclin-mediated pathway in neonatal rat cardiomyocytes. Int J Cardiol 2011; 146: 145-52.
  • Acetyl-L-Carnitine. Altern Med Rev 1999; 4: 438-41.
  • Calabrese V, Giuffrida Stella AM, Calvani M, Butterfield DA.Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes. J Nutr Biochem 2006; 17: 73-88.
  • Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol 2011; 110: 935-42.
  • Doroshow JH, Tallent C, Schechter JE. Ultrastructural Features of AdriamycinInduced Skeletal and Cardiac Muscle Toxicity. Am J Pathol 1985; 118: 288-97.
  • Çullu E, Özkan I, Çulhacı N, Alparslan B, Dikicioğlu E, Şavk SÖ. Doksorubisinin sıçan iskelet kasında kemomiyektomi etkisi. Acta Orthop Traumatol Turc 2003; 37: 323-9.
  • Deng S, Wojnowski L. Genotyping the risk of anthracycline-induced cardiotoxicity. Cardiovasc Toxicol 2007; 7: 129-34.
  • Berthiaume JM, Wallace KB. Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 2007; 23: 15-25.
  • Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review. Health Technol Assess 2007; 11: iii, ix-x.
  • Bast A, Haenen GR, Bruynzeel AM, Van der Vijgh WJ. Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials. Cardiovasc Toxicol 2007; 7: 154-9.
  • Kaiserová H, Simunek T, Sterba M, den Hartog GJ, Schröterová L, Popelová O, Gersl V, Kvasnicková E, Bast A. New iron chelators in anthracycline-induced cardiotoxicity. Cardiovasc Toxicol 2007; 7: 145-50.
  • Zeidán Q, Strauss M, Porras N, Anselmi G. Differential long-term subcellular responses in heart and liver to adriamycin stress. Exogenous L-carnitine cardiac and hepatic protection. J Submicrosc Cytol Pathol 2002; 34; 315-21.
  • Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep 1978; 62: 955-61.
  • Hirano S, Wakazono K, Agata N, Iguchi H, Tone H. Comparison of cardiotoxicity of pirarubicin, epirubicin and doxorubicin in the rat. Drugs Exp Clin Res 1994; 20: 153-60.
There are 22 citations in total.

Details

Primary Language Turkish
Journal Section Basic Science Research Articles
Authors

Hülya Tosun Yıldırım

Gülden Diniz

Safiye Aktaş

Nur Olgun

Publication Date January 30, 2013
Published in Issue Year 2013Volume: 35 Issue: 2

Cite

AMA Tosun Yıldırım H, Diniz G, Aktaş S, Olgun N. Asetil L-karnitin ve doksorubisinin rat çizgili kası üzerine etkilerinin araştırılması. CMJ. June 2013;35(2):166-171.