Exposing cardiomyocytes to subclinical concentrations of doxorubicin rapidly reduces their creatine transport

Marcus D. Darrabie, Antonio Jose Luis Arciniegas, Jose Gabriel Mantilla, Rajashree Mishra, Miguel Pinilla Vera, Lucia Santacruz, Danny O. Jacobs

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Doxorubicin is commonly used to treat leukemia, lymphomas, and solid tumors, such as soft tissue sarcomas or breast cancer. A major side effect of doxorubicin therapy is dose-dependent cardiotoxicity. Doxorubicin's effects on cardiac energy metabolism are emerging as key elements mediating its toxicity. We evaluated the effect of doxorubicin on [ 14C]creatine uptake in rat neonatal cardiac myocytes and HL-1 murine cardiac cells expressing the human creatine transporter protein. A significant and irreversible decrease in creatine transport was detected after an incubation with 50-100 nmol/l doxorubicin. These concentrations are well below peak plasma levels (5 μmol/l) and within the ranges (25-250 nmol/l) for steady-state plasma concentrations reported after the administration of 15-90 mg/m 2 doxorubicin for chemotherapy. The decrease in creatine transport was not solely because of increased cell death due to doxorubicin's cytotoxic effects. Kinetic analysis showed that doxorubicin decreased V max, K m, and creatine transporter protein content. Cell surface biotinylation experiments confirmed that the amount of creatine transporter protein present at the cell surface was reduced. Cardiomyocytes rely on uptake by a dedicated creatine transporter to meet their intracellular creatine needs. Our findings show that the cardiomyocellular transport capacity for creatine is substantially decreased by doxorubicin administration and suggest that this effect may be an important early event in the pathogenesis of doxorubicin-mediated cardiotoxicity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number5
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

Fingerprint

Creatine
Cardiac Myocytes
Doxorubicin
Biotinylation
Proteins
Sarcoma
Energy Metabolism
Lymphoma
Leukemia
Cell Death
Breast Neoplasms
Drug Therapy
creatine transporter

Keywords

  • Cardiac energy metabolism
  • Cardiotoxicity
  • Phosphocreatine

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Exposing cardiomyocytes to subclinical concentrations of doxorubicin rapidly reduces their creatine transport. / Darrabie, Marcus D.; Arciniegas, Antonio Jose Luis; Mantilla, Jose Gabriel; Mishra, Rajashree; Vera, Miguel Pinilla; Santacruz, Lucia; Jacobs, Danny O.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 303, No. 5, 01.09.2012.

Research output: Contribution to journalArticle

Darrabie, Marcus D. ; Arciniegas, Antonio Jose Luis ; Mantilla, Jose Gabriel ; Mishra, Rajashree ; Vera, Miguel Pinilla ; Santacruz, Lucia ; Jacobs, Danny O. / Exposing cardiomyocytes to subclinical concentrations of doxorubicin rapidly reduces their creatine transport. In: American Journal of Physiology - Heart and Circulatory Physiology. 2012 ; Vol. 303, No. 5.
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