Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury.
A major drawback to doxorubicin as a cancer-treating drug is cardiac toxicity. To understand the mechanism of doxorubicin cardiac toxicity and the potent synergic effect seen when doxorubicin is combined with anti-ErbB2 (trastuzumab), we developed an in vivo rat model that exhibits progressive dose-dependent cardiac damage and loss of cardiac function after doxorubicin treatment. The hearts of these animals respond to doxorubicin damage by increasing levels of ErbB2 and the ErbB family ligand, neuregulin 1beta, and by activating the downstream Akt signaling pathway. These increases in ErbB2 protein levels are not due to increased ErbB2 mRNA, however, suggesting post-transcriptional mechanisms for regulating this protein in the heart. Accordingly, levels of heat shock protein 90 (HSP90), a known ErbB2 protein stabilizer and chaperone, are increased by doxorubicin treatment, and coimmunoprecipitation reveals binding of HSP90 to ErbB2. Isolated cardiomyocytes are more susceptible to doxorubicin after treatment with HSP90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin, suggesting that the HSP90 is protective during doxorubicin treatment. Thus, our results provide one plausible mechanism for the susceptibility of the heart to anti-ErbB2 therapy post-doxorubicin therapy in subclinical and clinical conditions. Additionally, these results suggest that further testing is needed for HSP90 inhibitors under various conditions in the heart.
Gabrielson
Kathleen
K
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 Broadway, Baltimore, MD 21205, USA. kgabriel@jhmi.edu
Bedja
Djahida
D
Pin
Scott
S
Tsao
Allison
A
Gama
Lucio
L
Yuan
Bibo
B
Muratore
Nicole
N
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D016227:Benzoquinones / Q000494:pharmacology; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004317:Doxorubicin; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; C112765:tanespimycin