Contents

📒 Octavia 2012

Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies1

Sciwheel.

Molecular mechanism

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Mitochondrial dependent ROS

  • cationic drug doxorubicin is retained in the mitochondrial inner membrane (IMM) by forming a nearly-irreversible complex with cardiolipin
    • Inhibiting ETC complexes
  • doxorubicin treatment affects mitochondrial gene expression & suppresses cardiac mitochondrial metabolism and biogenesis
  • Upregulation of manganese superoxide dismutase (MnSOD): increase survival

NOS (NO synthase) dependent ROS

  • Binding of doxorubicin to endothelial NOS (eNOS) reductase domain (eNOS uncoupling) results in superoxide generation, related to doxorubicin-induced apoptosis
  • Inducible NOS (iNOS): controversial

NAD(P)H-dependent ROS

  • doxorubicin and NAD(P)H can produce a little superoxide in the absence of any enzymatic activity
  • NAD(P)H oxidase as another source

Fe – DOX complex

  • DOX decreases iron sequenster expression => more free iron => (DOX binds to iron) => toxicity
  • redox cycling => lipid peroxidation, protein (thiol group) oxidation

Apoptosis

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  • By oxidative stress

Intracellular calcium dysregulation

  • Both a result and a cause of ROS-generation.

Changes in the high-energy phosphate pool

  • Depletion of ATP/ PCr, depolarizations of mitochondria due to oxidative stress
  • Creatine kinase (CK) is inhibited by ROS

Endothelin-1 (ET-1)

  • survival signaling in CMCs counteracted by the vasoconstrictive effects of endothelin-1 on the vasculature

Extracellular matrix remodeling

  • Inhibits MMP-1 (less tumor cell metastasis), enhances MMP-2, MMP-9 in the heart => tissue remodeling

Symptoms and diagnostic tools

  • acute, subacute and late toxicity
  • Acute: usually resolve spontaneously within several hours or weeks after the completion of chemotherapy in most patients
  • subacute: rare
  • Chronic: dose-dependent, monitored by trponin, LVEF…

Therapeutic and preventive possibilities

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  • most effective: modulating the dosage.
  • Dexrazoxane: competes Top 2β binding => prevents depletion of mitochondrial DNA
  • β-blocker / ACEi/ ARB: when HF is indicated
  • EPO?
  • Preventive administration of sildenafil, a phosphodiesterase (PDE) 5 inhibitor
    • mitochondrial KATP channel opening
    • NOS-dependent
    • sildenafil and doxorubicin produce greater amounts of ROS in cancer cells. On the other hand, this combination produced less ROS in normal cells
  • cardiac resynchronization therapy (CRT): implant, for non-responser to cardioprotective medication
  • heart transplantation

Reference


  1. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol. 2012;52(6):1213-1225. doi:10.1016/j.yjmcc.2012.03.006. JMCC ↩︎