Doxorubicin effect on myocardial metabolism: a translational 18F-FDG PET/CT approach
Creators: name: BAUCKNEHT, MATTEO
Publisher: name: Universit� degli studi di Genova
Year: 2020

description: Systemic chemotherapy is the primary treatment for much diffuse solid neoplasms or hematological malignancies. One of its most significant drawbacks is the high incidence of side effects. Starting 30 years after treatment, the cumulative mortality from therapy-related medical illness exceeds the one from cancer recurrence. Besides secondary neoplasia, one of the most severe long-term complications is represented by cardiotoxicity that can significantly impact life expectancy, particularly in younger patients. One of the most acknowledged models of cardiotoxicity is represented by doxorubicin (DXR)-induced cardiomyopathy. Despite an extensive research effort, the mechanisms underlying this dose-dependent complication have not been fully elucidated, although a significant role has been proposed for oxidative stress. Together with the late onset of heart failure symptoms, this relative uncertainty prevents the availability of reliable methods to predict the risk of developing contractile dysfunction. In this line, several studies reported that myocardial uptake of the glucose analog 18F-fluorodeoxyglucose (FDG) increases during and after DXR administration. Similarly, GLUT-1 and GLUT-4 expression have been found to increase in a dose-dependent fashion, in neonatal rat ventricular cells exposed to DXR. Altogether, these observations seem to suggest that DXR might increase myocardial glucose consumption. However, an accelerated glycolytic flux in left ventricular myocardium has been usually reported during ischemia as a result of the impairment in oxidative phosphorylation and the consequent increase in the NADH cytosol level. By contrast, the increased expression of glucose carriers under DXR face a simultaneous evident oxidative damage to cardiomyocyte sarcolemma. On the other hand, we recently documented that FDG uptake in cancer cells is relatively independent of overall glucose consumption and selectively tracks the activity of a glucose-processing machine located within the endoplasmic reticulum and triggered by the autosomic enzyme hexose-6P-dehydrogenase (H6PD). The potential interest of this pathway is related to the observation that H6PD silencing, besides reducing FDG uptake, also caused a profound fall in the crucial cofactor for redox control NADPH. Whether confirmed to non-cancer cells, this finding might imply that FDG is a marker of cell?s anti-oxidative stress competency. Based on these considerations, the present Ph.D. project aimed to: 1. Characterize the direct redox and metabolic effect of Doxorubicin in cardiomyocytes. 2. Characterize the DXR cardiotoxic effect in experimental animals. 3. Characterize the DXR cardiotoxic impact on cancer patients. Obtained results showed that FDG PET/CT might represent an early predictor of subsequent cardiotoxicity in cancer patients treated with DXR. Moreover, the application of PET/CT may also extend beyond the mere cardiotoxicity identification providing mechanistic insight on the cardiotoxic pathophysiology. Indeed, this tool further enriched the current knowledge on energy metabolism impairment in the DXR-induced cardiotoxic cascade.