Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling
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 lin...
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MDPI AG
2021-04-01
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| author | Giedrė Valiulienė Aida Vitkevičienė Giedrė Skliutė Veronika Borutinskaitė Rūta Navakauskienė |
| author_facet | Giedrė Valiulienė Aida Vitkevičienė Giedrė Skliutė Veronika Borutinskaitė Rūta Navakauskienė |
| author_sort | Giedrė Valiulienė |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:17:50Z |
| format | Article |
| id | doaj.art-eb5980dd9f7d4ea3a1aab4ca3e7d2acf |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T12:17:50Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-eb5980dd9f7d4ea3a1aab4ca3e7d2acf2023-11-21T15:46:32ZengMDPI AGMolecules1420-30492021-04-01268230310.3390/molecules26082303Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox RemodelingGiedrė Valiulienė0Aida Vitkevičienė1Giedrė Skliutė2Veronika Borutinskaitė3Rūta Navakauskienė4Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, LT-01257 Vilnius, LithuaniaDepartment of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, LT-01257 Vilnius, LithuaniaDepartment of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, LT-01257 Vilnius, LithuaniaDepartment of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, LT-01257 Vilnius, LithuaniaDepartment of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Sauletekio av. 7, LT-01257 Vilnius, LithuaniaMetabolic 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.https://www.mdpi.com/1420-3049/26/8/2303acute myeloid leukemia (AML)metforminMCL-1 inhibitor S63845reactive oxygen species (ROS) |
| spellingShingle | Giedrė Valiulienė Aida Vitkevičienė Giedrė Skliutė Veronika Borutinskaitė Rūta Navakauskienė Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling Molecules acute myeloid leukemia (AML) metformin MCL-1 inhibitor S63845 reactive oxygen species (ROS) |
| title | Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling |
| title_full | Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling |
| title_fullStr | Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling |
| title_full_unstemmed | Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling |
| title_short | Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling |
| title_sort | pharmaceutical drug metformin and mcl1 inhibitor s63845 exhibit anticancer activity in myeloid leukemia cells via redox remodeling |
| topic | acute myeloid leukemia (AML) metformin MCL-1 inhibitor S63845 reactive oxygen species (ROS) |
| url | https://www.mdpi.com/1420-3049/26/8/2303 |
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