Abstract
Metabolic landscape and sensitivity to apoptosis induction play a crucial role in acute myeloid leukemia (AML) resistance. Therefore, we investigated the effect of metformin, a medication that also acts as an inhibitor of oxidative phosphorylation (OXPHOS), and MCL-1 inhibitor S63845 in AML cell lines NB4, KG1 and chemoresistant KG1A cells. The impact of compounds was evaluated using fluorescence-based metabolic flux analysis, assessment of mitochondrial Δψ and cellular ROS, trypan blue exclusion, Annexin V-PI and XTT tests for cell death and cytotoxicity estimations, also RT-qPCR and Western blot for gene and protein expression. Treatment with metformin resulted in significant downregulation of OXPHOS; however, increase in glycolysis was observed in NB4 and KG1A cells. In contrast, treatment with S63845 slightly increased the rate of OXPHOS in KG1 and KG1A cells, although it profoundly diminished the rate of glycolysis. Generally, combined treatment had stronger inhibitory effects on cellular metabolism and ATP levels. Furthermore, results revealed that treatment with metformin, S63845 and their combinations induced apoptosis in AML cells. In addition, level of apoptotic cell death correlated with cellular ROS induction, as well as with downregulation of tumor suppressor protein MYC. In summary, we show that modulation of redox-stress could have a potential anticancer activity in AML cells.
Highlights
Acute myeloid leukemia (AML) is one of the most common forms of blood cancer in adults
Effect of 10 mM metformin was of comparable degree between all cell lines, though metformin had a slightly stronger effect on cell viability in NB4 cells compared to KG1A cells
In order to reach a similar effect in KG1 cells we had to use 100 nM of S63845, whereas in KG1A cells only 1000 nM of S63845 could slow down the cell proliferation
Summary
Acute myeloid leukemia (AML) is one of the most common forms of blood cancer in adults. The prognosis of specific AML cases varies widely as patient age and type of AML should be taken into account. APL (acute promyelocytic leukemia) subtype of AML is mostly well managed, while others have a more complicated prognosis, as AML resistance and relapse still remain very serious issues [2]. Metformin (N,Ndimethylbiguanide), which is applied widely to treat the symptoms of hyperglycemia in type 2 diabetes [3] and used in the treatment of polycystic ovary syndrome [4], may be repurposed to manage cancer as well. We demonstrated that metformin in combination with cytarabine, and venetoclax slightly inhibited AML patients’ cell proliferation and profoundly reduced oxidative phosphorylation (OXPHOS) rate ex vivo [9]. It has been reported consistently that metformin elicits its effect on oxidative phosphorylation via inhibition of Complex I [10]
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