Doxorubicin cardiomyopathy via TLR-2 stimulation: potential for prevention using current anti-retroviral inhibitors such as ritonavir and nelfinavir.
Doxorubicin remains a useful anti-cancer drug but as lifetime dose approaches 500 mg/m2 and particularly when this dose is exceeded, iatrogenic life-threatening cardiomyopathy becomes progressively more likely. This note reviews evidence indicating that doxorubicin induced cardiomyopathy is partly mediated by stimulation of Toll-like receptors (TLR) 2 and 4 which are expressed on cardiomyocytes. Indinavir, nelfinavir, ritonavir, and saquinavir are currently marketed protease inhibitors used to suppress human immunodeficiency virus. They have recently been shown to inhibit signalling at TLR 2 and 4 as well as intracellular events downstream from these receptors. It is possible that these FDA-approved anti-retroviral protease inhibitors could be used off-label to diminish likelihood of doxorubicin cardiotoxicity permitting higher doxorubicin doses. We suggest that currently marketed anti-viral protease inhibitors be investigated in animal models of doxorubicin cardiomyopathy and if such studies do indeed show protection, human studies be initiated.
Kast
R E
RE
Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA. rekast@email.com
Foley
K F
KF
Focosi
D
D
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced*; D004317:Doxorubicin / Q000633:toxicity*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors
D000903:Antibiotics, Antineoplastic; D017320:HIV Protease Inhibitors; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D004317:Doxorubicin; D019888:Nelfinavir; D019438:Ritonavir