| Doxorubicin (DOX) is a highly effective and broad-spectrum antitumor drug inclinic, but the cardiotoxicity restricts its clinical application. The adaptive effect andhormesis initiated by the low doses radiation (LDR), may be show a protective effecton subsequent radiochemotherapy-induced damage. The protective effect had beenpreliminary proved that LDR could prevent cardiotoxicity induced by doxorubicin atsome level in our previous study. The mechanisms of LDR’s protection againstdoxorubicin-induced cardiotoxicity are still unclear. The research in this paper carriedout the following works to make further clarification of the above mechanism.We divided5groups，including control group, sham-irradiation group (0mGy),LDR group (75mGy), DOX group and LDR-72h-DOX group (with intraperitonealinjection of doxorubicin after72h LDR).To assess the potential protective effect of LDR on doxorubicin-inducedcardiotoxicity, we observed the general status of the mice, the survival rate,electrocardiogram, activity of serum myocardial enzymes and cardiachistopathological. The results showed that the general status and survival rate werepoor in the DOX group. Doxorubicin induced significantl ECG abnormalities,incremental activity of serum myocardial enzymes, cytoplasmic vacuolization andmyofibrillar disorder of cardiac tissue. However, with pretreatment of LDR, thegeneral status improved, the survival rate increased, enzymes activities decreased,ECG slightly changed, and cytoplasmic vacuolization relieved. All these changesindicated that LDR show effective protection against doxorubicin-inducedcardiotoxicity.In order to study the effect of LDR on doxorubicin-induced oxidative stress inmyocardial tissue, reactive oxygen species (ROS) levels was detected by flowcytometry and the level in myocardial homogenate malondialdehyde (MDA),superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-PX) activity were also detected. The results showed that doxorubicin induced the significantincrease of ROS and MDA lever in myocardial tissue, and decrease of SOD andGSH-PX activity. And with the pretreatment of LDR, it significantly increasedenzyme activities and decreased the level of ROS and MDA, however after theseparate LDR, the ROS level increased but the MDA had not significantly variationcompared with the sham-irradiation group. This result suggests that LDR is likely toagainst doxorubicin-induced cardiotoxicity through inhibiting doxorubicin-inducedoxidative stress in myocardial tissue by inducing the pre-adaptation of myocardialcells.So as to study the effect of LDR on doxorubicin-induced myocardial apoptosis,the apoptosis of cardiomyocyte was detected by TUNEL, the expression of Caspase3,Caspase9, Bax and Bcl-2were detected with immunohistochemistry method, andmitochondrial membrane potential (ΔΨm) was detected by flow cytometry. The resultshowed that doxorubicin induced ΔΨm depressed, the expression of Caspase3,Caspase9and Bax significantly increased and the expression of Bcl-2significantlydecreased, myocardial apoptosis significantly increased ultimately. With pretreatmentof LDR, ΔΨm increased; the expression of Caspase3, Caspase9, Bax decreased andthe expression of Bcl-2increased, myocardial apoptosis induced by doxorubicindecreased. However, in the LDR group, there was no discrepancy in above contentscompared to the sham-irradiation group. The results indicated that LDR can againstdoxorubicin-induced myocardial apoptosis, in which LDR might play a protectiveeffect through mitochondrial pathway by inducing the pre-adaptation of myocardialcells.In conclusion, LDR can induce the pre-adaptation of myocardial cells, thenagainst doxorubicin-induced myocardial cells injury. It showed that with thepretreatment of LDR, it may against doxorubicin-induced apoptosis of myocardialcells via suppression of oxidative stress and mitochondrial-dependent apoptosispathway. LDR is expected to be an assistant treatment in cardioprotective applied toantitumor therapy with doxorubicin. |
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