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Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Bedja, Djahida Pin, Scott Tsao, Allison L. Gama, Lucio Yuan, Bibo Muratore, Nicole |
| Copyright Year | 2007 |
| Abstract | 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/67/4/1436.full.pdf |
| PubMed reference number | 17308081v1 |
| Volume Number | 67 |
| Issue Number | 4 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Adverse reaction to drug Cardiotoxicity Doxorubicin ERBB2 protein, human ErbB Receptors HSP72 Heat-Shock Proteins HSP90 Heat-Shock Proteins Heart Diseases Heat shock proteins Heat-Shock Response Ligands Molecular Chaperones Myocytes, Cardiac Neoplasms Neuregulins Proto-Oncogene Proteins c-akt Signal Transduction Pathways Transcription, Genetic tanespimycin trastuzumab |
| Content Type | Text |
| Resource Type | Article |
