Latent cardiotoxicity occurs in children who receive low doses of anthracyclines (e.g. doxorubicin, DOX) and can be exacerbated by other cardiovascular risk factors. Psychosocial stress is a significant cardiovascular risk factor and an enormous burden in childhood cancer survivors. Although observational studies showed that psychosocial stress is associated with higher rates of cardiovascular complications in cancer survivors, the mechanism of this association has not been elucidated. To fill this gap in knowledge, these researchers have developed a “two-hit” mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by psychosocial stress leading to overt cardiomyopathy.
The overall objective of this project is to determine the molecular mechanisms of DOX/stress-induced cardiomyopathy and to test treatments that can prevent it. Preliminary data demonstrated that exposure of juvenile mice to a low, yet clinically relevant, dose of DOX (4 mg/kg/week for 3 weeks) activated cardiac p38 mitogen-activated protein kinase (MAPK) and induced the senescence marker p21. After a 5-week recovery period, DOX-exposed mice manifested exaggerated myocardial fibrosis and increased expression of the senescence marker p21 and senescence-associated secretory pattern (SASP) when challenged with a validated model of chronic psychosocial stress. Senolytic therapy with ABT-263 abrogated these effects.
The central hypothesis of this project is that psychosocial stress will exacerbate DOX-induced cardiovascular aging to precipitate overt cardiomyopathy via a p38/senescence-mediated mechanism. The project has three aims:
- Test the hypothesis that DOX (4 mg/kg/week for 3 weeks) will activate p38-dependent cardiovascular aging leading to latent cardiotoxicity. DOX-induced cardiovascular aging will be prevented by the p38-selective inhibitor losmapimod and the pleiotropic phytochemical resveratrol, and will be reversed by the senolytic drug ABT-263.
- Test the hypothesis that psychosocial stress (14-day sensory contact with a dominant animal, and daily 10-minute defeat episodes) will exacerbate DOX-induced activation of senescence, inflammatory, and fibrotic pathways leading to overt cardiomyopathy, an effect that will be limited by losmapimod, ABT-263, and resveratrol.
- Characterize the effects of DOX +/- losmapimod, ABT-263, and resveratrol on cardiovascular function and markers of cardiovascular aging in immunocompetent EL4 lymphoma tumor-bearing mice. The effect of these agents on the chemotherapeutic benefit of DOX in the tumor-bearing mice will then be determined.