.hsir2/sirt1 Reduce The Cardiotoxicity Of The Anthracycline Class Of Anticancer Drugs Doxorubicin

Doxorubicin, a widely used chemotherapy agents in clinic, can penetrate through cell membrane into the cell and combine with chromosome. It exerts its anti-tumor effects through forming a complex with DNA double strand and strongly interfering DNA synthesis, RNA synthesis and also protein synthesis. The application of doxorubicin is limited because of the side effects to health organisms, among which the dose-dependent heart failure is most significant.An attractive mechanism of doxorubicin-induced cardio-toxicity involves the apoptosis of cardiac myocytes. Doxorubicin is known to result in generation of cellular oxidative stress, and this has been proposed as a proximal step leading to myocyte cell death. Another possible mechanism is doxorubicin-induced sarcomere disruption. Since the integrity of the myocyte sarcomere is intrinsic to myocyte function, loss or disorganization of the cardiac sarcomere presumably leads to impaired cardiac function and cardiomyopathy.Previous work from our lab has already demonstrated that the NAD+ dependent classlll deacetylase SIRT1 plays a role in cadiomyocyte survival and apoptosis. Moderate overexpression of SIRT1 potentiates cardiomyocyte's ability to counteract hypertrophy and aging. SIRT1 also promotes survival in various cells and organisms because of its anti-oxidative stress and anti-apoptotic effects. Based on the beneficial effects of SIRT1, we hypothesize that SIRT1 may protect cardiomyocytes against doxorubicin-induced apoptosis.To verify our hypothesis, we treated neonatal rat cardiomyocytes and H9C2 cells with doxorubicin and found that the expression level of SIRT1 was first upregulated and then down regulated. The level of the apoptosis marker cleaved caspase3 was gradually increased. When SIRT1's expression level was downregulated, the cleaved caspase3 level showed a rapid rise. The results indicated that SIRT1 may play a role in the process.To clarify SIRT1's effect, we constructed and packaged SIRT1 overexpression and RNAi adenovirus to change the SIRT1 level in cardiomyocytes. We found that SIRT1 overexpression reduced the apoptosis level of cardiomyocyte in a dose dependent mamner after treated with doxorubicin. Meanwhile, when knockdown of SIRT1 by SIRT1 RNAi, more dead cardiomyocytes were observed after treated with doxorubicin. The results demonstrate that both exogenous and endogenous SIRT1 protect cardiomyocytes against doxorubicin-induced apoptosis.When administrated with doxorubicin, mice will have acute toxicity response. To elucidate SIRT1's effect in this process, we treated cardiac specific SIRT1H363Y transgenic mice with doxorubicin. We found that, when endogenous SIRT1 was inhibited, mice were more sensitive to doxorubicin toxicity and the survival rate of the transgenic mice was obviously lower. The results indicate that SIRT1 also protect mice against doxorubicin-induced acute toxicity.Our research, for the first time, demonstrated that SIRT1 protects cardiomyocytes against doxorubicin-induced apoptosis and we also showed that SIRT1 has obvious protective effect in doxorubicin-induced mice acute cardiac toxicity. The beneficial effects of SIRT1 in the process provide new insights in reducing side effects of chemotherapy agents in clinic.