Heat Shock Protein 90 and ErbB2 in the Cardiac Response to Doxorubicin Injury

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 1B, 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. [Cancer Res 2007;67(4):1436-41]

ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity

“…Clinical studies using radiolabeled anti-ErbB2 and SPECT imaging showed that more anti-ErbB2 binds in the heart after doxorubicin treatment (3). These clinical studies are in agreement with our earlier findings that doxorubicin increases ErbB2 in the rat heart (19). In the current study, our findings that GPx and catalase activities are elevated additionally support the antioxidant role of ErbB2.…”

“…The clinical link between ErbB2 and heart function was discovered when 27% of ErbB2-overexpressing breast cancer patients treated with doxorubicin and anti-ErbB2 (Trastuzumab/Herceptin) subsequently developed a synergistic cardiac toxicity (57,65). We previously reported that doxorubicin treatment induces the expression of ErbB2 in rat heart (19), but it is still unknown whether this ErbB2 upregulation might serve to counteract oxidative stress induced by doxorubicin. If so, an upregulation of ErbB2 protein in cardiomyocytes could represent a molecular target for anti-ErbB2 therapy to reverse any cardioprotective mechanisms attributed by ErbB2.…”

Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice

“…In agreement with previous studies and in line with the findings derived from human studies, doxorubicin in our model led to severely reduced LV systolic and diastolic function, which consequently resulted to decreased global heart function as indexed by suppressed CO (8,20). The inhibition of HMG-CoAreductase by pretreatment with fluvastatin improved LV function under these conditions.…”

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

“…Images are representative from three different cell preparations. Scale bar corresponds to 10 μm vitro studies using primary cardiomyocytes (Gabrielson et al 2007;Solem et al 1996;Zhou et al 2001) or other cell lines (L'Ecuyer et al 2001;Spallarossa et al 2004) have been widely reported in the literature. From the different models used, some conclusions are common to all: (a) Dox is activated at the mitochondrial level, forming a semiquinone radical, and (b) Dox causes oxidative stress in cardiac cells that particularly affects mitochondria (Berthiaume and Wallace 2007;Wallace 2003).…”