Geranylgeranylacetone blocks doxorubicin-induced cardiac toxicity and reduces cancer cell growth and invasion through RHO pathway inhibition.

Doxorubicin is a widely used chemotherapy for solid tumors and hematologic malignancies, but its use is limited due to cardiotoxicity. Geranylgeranylacetone (GGA), an antiulcer agent used in Japan for 30 years, has no significant adverse effects, and unexpectedly reduces ovarian cancer progression in mice. Because GGA reduces oxidative stress in brain and heart, we hypothesized that GGA would prevent oxidative stress of doxorubicin cardiac toxicity and improve doxorubicin's chemotherapeutic effects.

Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice.

Background: Emerging evidence shows that ErbB2 signaling has a critical role in cardiomyocyte physiology, based mainly on findings that blocking ErbB2 for cancer therapy is toxic to cardiac cells. However, consequences of high levels of ErbB2 activity in the heart have not been previously explored.

Methodology/principal Findings: We investigated consequences of cardiac-restricted over-expression of ErbB2 in two novel lines of transgenic mice.

Detection of dose response in chronic doxorubicin-mediated cell death with cardiac technetium 99m annexin V single-photon emission computed tomography.

The aim of this study was to evaluate whether technetium 99m hydrazinonicotinamide (99mTc-HYNIC)-annexin V single-photon emission computed tomography (SPECT) would detect dose-dependent doxorubicin (DOX)-mediated cell death in the heart compared with functional echocardiography. Adult female Sprague-Dawley rats were treated with DOX (cumulative dose of 15 or 7.5 mg/kg) or saline (n = 7) and monitored by echocardiography.

Effects of bedding substrates on microsomal enzymes in rabbit liver.

Previous studies have reported that housing rats and mice on softwood beddings induce microsomal enzymes. To date, no published studies investigate effects of softwood beddings on microsomal induction in rabbits. The purpose of this study was to determine whether microsomal enzymes, primarily cytochromes P450 3A and 2B, were induced in rabbits exposed to commonly used bedding substrates.

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.

Validation of the use of long-term indwelling jugular catheters in a rat model of cardiotoxicity.

Doxorubicin administered to rats induces a dose-dependent cardiomyopathy. Both doxorubicin administration and the presence of indwelling catheters have been associated with thrombus formation. We sought to determine feasibility of drug delivery and degree of thrombogenesis related to long-term indwelling catheter use in a cardiotoxicity model.

Sex differences in cell death.

Female patients experience substantial neuroprotection after experimental stroke compared with male patients, a finding attributed to the protective effects of gonadal hormones. This study examined the response of male- and female-derived organotypic hippocampal slices to oxidative and excitotoxic injury. Both oxygen and glucose deprivation and N-methyl-D-aspartic acid exposure led to neuronal death; however, female-derived cultures sustained less injury than male-derived cultures.