Background: Doxorubicin (DOX) is an anticancer drug used in the treatment of various malignant tumors. DOX has side effect of cardiotoxicity and development of preventive drug is necessary. Until now, no effective drug was discovered. One of proposing mechanism to reverse cardiotoxicity is trough reversing mitochondrial dysfunction caused by calmodulin kinase II (CamKII).
Objective: To establish molecular basis for the development of prophylactic agents for DOX-induced cardiotoxicity focusing on CamKII-Mitochondria pathway.
Method: DOX treatment was performed in H9C2 cells. Mitochondrial membrane potential (MMP) detected using JC-1 dye, cell that undergo mitophagy were detected by using Mitophagy detection dye. A specific inhibitor of CamKII activity, KN93 was used. we still prospecting result from western-blot and expression level.
Results: Doxorubicin-induced MMP damage was significantly suppressed by KN-93 treatment (red / green fluorescence signal ratio: control 3.1 ± 0.2, DOX 2.0 ± 0.3, KN-93 group 2.4 ± 0.5, P value <0.05, n = 12). Similarly, DOX-induced mitophagy was significantly suppressed by KN-93 treatment (mitophagy positive cells: control 58.0 ± 4.0%, DOX 58.0 ± 4.0%, KN-93 group 39.5 ± 8%, P value <0.05, n = 4).
Conclusion: DOX activates the CamKII and Drp-1 proteins and causes mitochondrial dysfunction due to mitochondrial injury and abnormal division of mitochondria. Molecules involved in the activation of CamKII and its signalling pathway are target molecules for the development of prophylactic agents for DOX-induced cardiotoxicity