RESUMEN
Introduction: Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats. Methods: Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment. Results and discussion: GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.
RESUMEN
Cancer remains a worldwide cause of morbidity and mortality. Investigational research efforts have included the administration of tumor-derived extracts to healthy animals. Having previously demonstrated that the administration of non-transmissible, human cancer-derived homogenates induced malignant tumors in mice, here, we examined the consequences of administering 50 or 100 µg of protein of crude homogenates from mammary carcinoma, pancreatic adenocarcinoma, and melanoma samples in 6 inoculations per week during 2 months. The concurrent control mice received homogenates of healthy donor-skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke the deterioration or mortality of the animals. Multiple foci of lung adenocarcinomas with a broad expression of malignity histomarkers coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers, were detected in lymphoid nodes. The administration of pancreatic tumor and melanoma homogenates progressively deteriorated animal health. Pancreatic tumor induced poorly differentiated lung adenocarcinomas and pancreatic islet hyperplasia. Melanoma affected lungs with solid pseudopapillary adenocarcinomas. Giant atypical hepatocytes were also observed. The kidney exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. Nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in the control mice. Furthermore, the incubation of zebrafish embryos with breast tumor homogenates induced the expression of c-Myc and HER-2 as tumor markers, contrasting to embryos exposed to healthy tissue-derived material. This study confirms and extends our hypothesis that tumor homogenates contain and may act as vectors for "malignancy drivers," which ultimately implement a carcinogenesis process in otherwise healthy mice.