Involvement of mitochondrial dynamics in the antineoplastic activity of cisplatin in murine leukemia L1210 cells

Abstract

Leukemia is a type of hematopoietic stem cell malignant cloned disease with high mortality. Cisplatin-based chemotherapy is one of the most common treatments for leukemia. Similar to other chemotherapeutic agents, cisplatin resistance has become a serious issue in cancer therapy. In the present study, we investigated the role of mitochondrial dynamics in the antineoplastic activity of cisplatin in murine leukemia L1210 cells. Firstly, the L1210 cell line resistant to cisplatin (L1210/DDP) was established. Compared to its parental cell line, the IC50 value of cisplatin in the L1210/DDP cells was increased 10-fold. Mitofusins (Mfn1 and Mfn2), mitochondrial outer membrane fusion proteins, were markedly upregulated in the L1210/DDP cells, whereas the expression of fission protein Drp1 and inner membrane fusion protein OPA1 were not significantly altered. In addition, mitofusins were also upregulated in the parental L1210 cells subjected to cisplatin stress. To investigate the role of mitochondrial dynamics in the antineoplastic activity of cisplatin, the effect of mitochondrial division inhibitor (Mdivi)-1 on cisplatin‑induced cell death, caspase-3 cleavage and ROS production was examined in L1210 cells. We found that 5 µM of Mdivi-1 efficiently attenuated cisplatin-induced cell death, caspase activation and intracellular ROS increase in L1210 cells. Our data indicated that mitochondrial dynamics play an important role in the antineoplastic activity of cisplatin, and mitofusin-mediated mitochondrial fusion may be involved in the process of cisplatin resistance in leukemia cells. Therefore, the present study revealed that mitochondrial dynamics may be a potential target used to improve the antineoplastic activity of cisplatin in leukemia in the future.

Mitochondrial Dynamics in Type 2 Diabetes and Cancer

“…For instance, hepatocellular carcinoma ( 45 ), osteosarcoma ( 46 ), medulloblastoma ( 47 ), thyroid ( 42 ), colorectal ( 48 ), endometrial ( 49 ), and breast cancer ( 43 ) show increased mitochondrial fragmentation, due to upregulation of DRP1 levels and a concomitant reduction in MFN1/2 levels. On the other hand, tumors of the prostate ( 50 ), neuroblastoma ( 51 ), leukemia ( 52 ), glioblastoma ( 53 ), and lung ( 54 ) are associated with downregulation of DRP1 and increased MFN1/2 levels. What could be driving these contrasting preferences of fission versus fusion of the mitochondrial networks in cancer?…”

“…Furthermore, mdivi-1 induced cell death ( 75 ) and synergized apoptotic effects of platinum agents in drug resistant ovarian tumor cells ( 79 ). However, mdivi-1 prevents apoptosis induced by cisplatin in breast cancer ( 68 ) and leukemia ( 52 ). As discussed above, these controversial results suggest that mdivi-1 can act either as pro- or anti-apoptotic agent, depending on the cell types and apoptotic stimuli in question [reviewed in Ref.…”

The Effect of Allogeneic Mesenchymal Stem Cell Transplantation on the Activity of Mitochondrial Succinate Dehydrogenase in the Liver of Recipient Animals

“…СДГ вищих організмів має здатність каталізувати також зворотню реакцію (фумаратредуктазну) -відновлення фумарової кислоти до сукцинату. Донорами у цій реакції є убіхіноли, флавінмононуклеотиди тощо (Sun, 2005;Han, 2017). Активність СДГ є маркерним параметром функціонального стану мітохондрій.…”

Peer Review #2 of "Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups (v0.2)"

“…Currently, evidence demonstrates that the mitochondria may also affect an individual's response to cisplatin treatment (Han et al 2017;Marrache et al 2014;Marullo et al 2013;Tsuyoshi et al 2017). Mitochondria are organelles that play an important role in ATP production, calcium homeostasis, cell signaling, and apoptosis.…”