Geranylgeranylacetone blocks doxorubicin-induced cardiac toxicity and reduces cancer cell growth and invasion through RHO pathway inhibition
Menée à l'aide de modèles murins, cette étude évalue l'intérêt d'un anti-ulcéreux utilisé au Japon depuis 30 ans (géranylgéranylacétone) pour réduire la toxicité cardiaque associée à la doxorubicine, et améliorer son efficacité, dans le traitement des cancers du sein
Doxorubicin is a widely used chemotherapy for solid tumors and hematological malignancies, but its use is limited due to cardiotoxicity. Geranylgeranylacetone (GGA), an anti-ulcer agent used in Japan for thirty years, has no significant adverse effects, and unexpectedly reduces ovarian cancer progression in mice. Since 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. Nude mice implanted with MDA-MB-231 breast cancer cells were studied after chronic treatment with doxorubicin, doxorubicin/GGA, GGA, or saline. Trans-thoracic echocardiography was used to monitor systolic heart function and xenografts evaluated. Mice were euthanized and cardiac tissue evaluated for reactive oxygen species generation, TUNEL assay and RHO/ROCK pathway analysis. Tumor metastases were evaluated in lung sections. In vitro studies using Boyden chambers were performed to evaluate GGA effects on RHO pathway activator lysophosphatidic acid (LPA) induced motility and invasion. We found that GGA reduced doxorubicin cardiac toxicity, preserved cardiac function, prevented TUNEL-positive cardiac cell death and reduced doxorubicin-induced oxidant production in a NOS-dependent and independent manner. GGA also reduced heart doxorubicin induced ROCK1 cleavage. Remarkably, in xenograft implanted mice, combined GGA/doxorubicin treatment decreased tumor growth more effectively than doxorubicin treatment alone. As evidence of anti-tumor effect, GGA inhibited LPA-induced motility and invasion by MDA-MB-231 cells. These anti-invasive effects of GGA were suppressed by geranylgeraniol suggesting GGA inhibits RHO pathway through blocking geranylation. Thus, GGA protects the heart from doxorubicin chemotherapy-induced injury and improves anti-cancer efficacy of doxorubicin in breast cancer.
http://mct.aacrjournals.org/content/early/2014/04/15/1535-7163.MCT-13-0965.abstract 2014