Involvements Of Mitochondrial Dynamics In Cisplatin-mediated Anti-leukemia And Resistance

Leukemia(also known as blood cancer), a kind of hematopoietic stem cells malignant cloned disease, is one of the top ten malignant tumors in China. Its main characteristic is that the leukemia cells unlimited proliferation in bone marrow and other hematopoietic tissue, thus affecting the generation of normal blood cells. It has been reported that the antitumor drug cisplatin has been used for curing leukemia, however, its mechanisms are not clear. Our results showed that cisplatin can promote apoptosis in mouse leukemia L1210 cell lines, whereas the inhibitor Mdivi-1 of mitochondrial dynamic related protein 1(Drp1) can markedly inhibit the alternations induced by cisplatin. In addition, cisplatin can activate caspase 3 pathway in L1210 cells, whereas Drp1 inhibitor Mdivi-1 can markedly inhibit the alternations induced by cisplatin. And after treated with cisplatin, the intracellular ROS concentrations were significantly increased in L1210 cells and however, Drp1 inhibitor Mdivi-1 effectively inhibited cisplatin-mediated production of ROS. The above experimental results indicated that the functional changes of the mitochondria dynamic related proteins play an important role in cisplatin-mediated anti-leukemia in L1210 cells. Although cisplatin has been widely used for treatment of leukemia clinically, the generation of cisplatin resistance is main reason for its failure of curing leukemia. To elucidate the possible mechanisms of the cisplatin resistance, we established a mouse lymphoid leukemia L1210 cell cisplatin resistance cell line that was referred to L1210/DDP, in which the cell lines were used to investigate the relationship between the generation of cisplatin resistance and mitochondrial dynamic changes. Our results showed that the expressions of mitochondrial outer membrane fusion regulating protein Mfn1 and Mfn2 were significantly increased in L1210/DDP cisplatin resistance cell line, suggesting that the generation of cisplatin resistance is related with the mitochondrial outer membrane fusion regulating proteins-mediated mitochondrial function changes.