Combination of Ethacrynic Acid and ATRA Triggers Differentiation and/or Apoptosis of Acute Myeloid Leukemia Cells through ROS


Cite item

Full Text

Abstract

Background and objective:All-trans retinoic acid (ATRA), an effective differentiation inducer, has been applied clinically to treat acute promyelocytic leukemia (APL). Unfortunately, it is not as potent in other kinds of acute myeloid leukemia (AML). Ethacrynic acid (EA), a classical powerful diuretic, can increase reactive oxygen species (ROS) contents, which can assist ATRA in inducing differentiation in AML cells. Here, we investigated the effect of EA combined with ATRA (EA+RA) on some AML cells except APL.

Methods:Apoptosis and differentiation were determined by morphology, cell viability, Annexin-V assay and CD11c expression. Western blot analysis and the detection of ROS and mitochondrial transmembrane potentials (MMP) were used to investigate the mechanisms.

Results:AML cells exhibited differentiation and/or apoptosis after EA+RA treatment. EA+RA increased the intracellular ROS contents. EA+RA-induced apoptosis was accompanied by MMP attenuation and caspase-3/7 activation. EA+RA-induced differentiation was along with MEK/ERK and Akt activation and increased expression of PU.1, CCAAT/enhancer-binding protein β (C/EBPβ) and C/EBPε. N-acetyl-L-cysteine (NAC), an antioxidant, thoroughly reduced EA+RA-increased ROS, and also inhibited MMP attenuation, the activation of caspase- 3/7, MEK/ERK and Akt pathways, the elevation of PU.1 and C/EBPs, and apoptosis and differentiation. However, MEK or PI3K specific inhibitors only suppressed EA+RA-triggered differentiation and the elevation of PU.1 and C/EBPs, but not ROS levels.

Conclusion:EA+RA induced cell apoptosis through ROS dependent MMP attenuation and caspase 3/7 activation while inducing differentiation by ROS-MEK/ERK-PU.1/C/EBPs and ROS-Akt-PU.1/C/EBPs pathways. In summary, it may provide innovative ATRA-based combination therapy strategies for AML patients via ROS.

About the authors

Xun Cai

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Author for correspondence.
Email: info@benthamscience.net

Lu Li

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

Hui-Min Xi

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

Hao Lu

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Email: info@benthamscience.net

References

  1. Bewersdorf, J.P.; Abdel-Wahab, O. Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic. Genes Dev., 2022, 36(5-6), 259-277. doi: 10.1101/gad.349368.122 PMID: 35318270
  2. Ni, X.; Hu, G.; Cai, X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit. Rev. Food Sci. Nutr., 2019, 59(S1), S71-S80. doi: 10.1080/10408398.2018.1509201
  3. Ricci, Z.; Haiberger, R.; Pezzella, C.; Garisto, C.; Favia, I.; Cogo, P. Furosemide versus ethacrynic acid in pediatric patients undergoing cardiac surgery: A randomized controlled trial. Crit. Care, 2015, 19(1), 2. doi: 10.1186/s13054-014-0724-5 PMID: 25563826
  4. Al-Dali, A.; Weiher, H.; Schmidt-Wolf, I. Utilizing ethacrynic acid and ciclopirox olamine in liver cancer. Oncol. Lett., 2018, 16(5), 6854-6860. doi: 10.3892/ol.2018.9472 PMID: 30405829
  5. Schmeel, L.C.; Schmeel, F.C.; Kim, Y.; Endo, T.; Lu, D.; Schmidt-Wolf, I.G. Targeting the Wnt/beta-catenin pathway in multiple myeloma. Anticancer Res., 2013, 33(11), 4719-4726. PMID: 24222106
  6. Von Schulz-Hausmann, S.A.; Schmeel, L.C.; Schmeel, F.C.; Schmidt-Wolf, I.G. Targeting the Wnt/beta-catenin pathway in renal cell carcinoma. Anticancer Res., 2014, 34(8), 4101-4108. PMID: 25075035
  7. Zhang, X.; Huang, C.; Cui, B.; Pang, Y.; Liang, R.; Luo, X. Ethacrynic acid enhances the antitumor effects of afatinib in EGFR/T790M-mutated NSCLC by inhibiting WNT/beta-catenin pathway activation. Dis. Markers, 2021, 2021, 1-17. doi: 10.1155/2021/5530673 PMID: 34122668
  8. Liu, B.; Huang, X.; Hu, Y.; Chen, T.; Peng, B.; Gao, N.; Jin, Z.; Jia, T.; Zhang, N.; Wang, Z.; Jin, G. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer. Oncotarget, 2016, 7(36), 58038-58050. doi: 10.18632/oncotarget.10846 PMID: 27487128
  9. Wang, R.; Liu, C.; Xia, L.; Zhao, G.; Gabrilove, J.; Waxman, S.; Jing, Y. Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: The role of glutathione S-transferase p1-1. Clin. Cancer Res., 2012, 18(24), 6690-6701. doi: 10.1158/1078-0432.CCR-12-0770 PMID: 23082001
  10. Makishima, M.; Honma, Y. Ethacrynic acid and 1α,25-dihydroxyvitamin D3 cooperatively inhibit proliferation and induce differentiation of human myeloid leukemia cells. Leuk. Res., 1996, 20(9), 781-789. doi: 10.1016/0145-2126(96)00050-1 PMID: 8947589
  11. Studzinski, G.P.; Bhandal, A.K.; Brelvi, Z.S. Cell cycle sensitivity of HL-60 cells to the differentiation-inducing effects of 1-alpha,25-dihydroxyvitamin D3. Cancer Res., 1985, 45(8), 3898-3905. PMID: 3860289
  12. Marcinkowska, E.; Vitamin, D. Vitamin D derivatives in acute myeloid leukemia: The matter of selecting the right targets. Nutrients, 2022, 14(14), 2851. doi: 10.3390/nu14142851 PMID: 35889808
  13. Ye, Z.; Zhang, X.; Zhu, Y.; Song, T.; Chen, X.; Lei, X.; Wang, C. Chemoproteomic profiling reveals ethacrynic acid targets adenine nucleotide translocases to impair mitochondrial function. Mol. Pharm., 2018, 15(6), 2413-2422. doi: 10.1021/acs.molpharmaceut.8b00250 PMID: 29763317
  14. Ma, H.Y.; Wang, C.Q.; He, H.; Yu, Z.Y.; Tong, Y.; Liu, G.; Yang, Y.Q.; Li, L.; Pang, L.; Qi, H.Y. Ethyl acetate extract of Caesalpinia sappan L. inhibited acute myeloid leukemia via ROS-mediated apoptosis and differentiation. Phytomedicine, 2020, 68, 153142. doi: 10.1016/j.phymed.2019.153142 PMID: 32045840
  15. Wu, G.; Liu, T.; Li, H.; Li, Y.; Li, D.; Li, W. c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation. Cell Death Dis., 2018, 9(5), 473. doi: 10.1038/s41419-018-0498-9 PMID: 29700286
  16. Agassi, S.F.T.; Yeh, T.M.; Chang, C.D.; Hsu, J.L.; Shih, W.L. Potentiation of differentiation and apoptosis in a human promyelocytic leukemia cell line by garlic essential oil and its organosulfur compounds. Anticancer Res., 2020, 40(11), 6345-6354. doi: 10.21873/anticanres.14655 PMID: 33109572
  17. Ogino, T.; Ozaki, M.; Matsukawa, A. Oxidative stress enhances granulocytic differentiation in HL 60 cells, an acute promyelocytic leukemia cell line. Free Radic. Res., 2010, 44(11), 1328-1337. doi: 10.3109/10715762.2010.503757 PMID: 20815781
  18. Li, Y.P.; Said, F.; Gallagher, R.E. Retinoic acid-resistant HL-60 cells exclusively contain mutant retinoic acid receptor-alpha. Blood, 1994, 83(11), 3298-3302. doi: 10.1182/blood.V83.11.3298.3298 PMID: 8193365
  19. Xi, H.M.; Lu, H.; Weng, X.Q.; Sheng, Y.; Wu, J.; Li, L.; Cai, X. Combined application of salinomycin and ATRA induces apoptosis and differentiation of acute myeloid leukemia cells by inhibiting WNT/β-catenin pathway. Anticancer. Agents Med. Chem., 2023, 23(9), 1074-1084. doi: 10.2174/1871520623666230110121629 PMID: 36627782
  20. Lu, H.; Weng, X.; Sheng, Y.; Wu, J.; Xi, H.; Cai, X. Combination of midostaurin and ATRA exerts dose-dependent dual effects on acute myeloid leukemia cells with wild type FLT3. BMC Cancer, 2022, 22(1), 749. doi: 10.1186/s12885-022-09828-2 PMID: 35810308
  21. Lu, H.; Li, Z.; Ding, M.; Liang, C.; Weng, X.; Sheng, Y.; Wu, J.; Cai, X. Trametinib enhances ATRA-induced differentiation in AML cells. Leuk. Lymphoma, 2021, 62(14), 3361-3372. doi: 10.1080/10428194.2021.1961231 PMID: 34355652
  22. Li, Z.Y.; Liang, C.; Ding, M.; Weng, X.Q.; Sheng, Y.; Wu, J.; Lu, H.; Cai, X. Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells. Am. J. Transl. Res., 2020, 12(12), 7836-7854. PMID: 33437364
  23. Lu, D.; Liu, J.X.; Endo, T.; Zhou, H.; Yao, S.; Willert, K.; Schmidt-Wolf, I.G.H.; Kipps, T.J.; Carson, D.A. Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway. PLoS One, 2009, 4(12), e8294. doi: 10.1371/journal.pone.0008294 PMID: 20011538
  24. Lacreta, F.P.; Brennan, J.M.; Nash, S.L.; Comis, R.L.; Tew, K.D.; O’Dwyer, P.J. Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer. J. Pharmacol. Exp. Ther., 1994, 270(3), 1186-1191. PMID: 7932170
  25. Yen, A.; Roberson, M.S.; Varvayanis, S.; Lee, A.T. Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. Cancer Res., 1998, 58(14), 3163-3172. PMID: 9679985
  26. Bertagnolo, V.; Neri, L.M.; Marchisio, M.; Mischiati, C.; Capitani, S. Phosphoinositide 3-kinase activity is essential for all-transretinoic acid-induced granulocytic differentiation of HL-60 cells. Cancer Res., 1999, 59(3), 542-546. PMID: 9973197
  27. Ray, P.D.; Huang, B.W.; Tsuji, Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal., 2012, 24(5), 981-990. doi: 10.1016/j.cellsig.2012.01.008 PMID: 22286106
  28. Zou, Z.; Chang, H.; Li, H.; Wang, S. Induction of reactive oxygen species: An emerging approach for cancer therapy. Apoptosis, 2017, 22(11), 1321-1335. doi: 10.1007/s10495-017-1424-9 PMID: 28936716
  29. Morana, O.; Wood, W.; Gregory, C.D. The apoptosis paradox in cancer. Int. J. Mol. Sci., 2022, 23(3), 1328. doi: 10.3390/ijms23031328 PMID: 35163253
  30. Isgrò, C.; Sardanelli, A.M.; Palese, L.L. Systematic search for SARS-CoV-2 main protease inhibitors for drug repurposing: Ethacrynic acid as a potential drug. Viruses, 2021, 13(1), 106. doi: 10.3390/v13010106 PMID: 33451132
  31. Autore, F.; Chiusolo, P.; Sorà, F.; Giammarco, S.; Laurenti, L.; Innocenti, I.; Metafuni, E.; Piccirillo, N.; Pagano, L.; Sica, S. Efficacy and tolerability of first line arsenic trioxide in combination with all-trans retinoic acid in patients with acute promyelocytic leukemia: Real life experience. Front. Oncol., 2021, 11, 614721. doi: 10.3389/fonc.2021.614721 PMID: 34336637
  32. Nitti, M.; Furfaro, A.L.; Cevasco, C.; Traverso, N.; Marinari, U.M.; Pronzato, M.A.; Domenicotti, C. PKC delta and NADPH oxidase in retinoic acid-induced neuroblastoma cell differentiation. Cell. Signal., 2010, 22(5), 828-835. doi: 10.1016/j.cellsig.2010.01.007 PMID: 20074641
  33. N’Diaye, E-N.; Vaissiere, C.; Gonzalez-Christen, J.; Grégoire, C.; Le Cabec, V.; Maridonneau-Parini, I. Expression of NADPH oxidase is induced by all-trans retinoic acid but not by phorbol myristate acetate and 1,25 dihydroxyvitamin D3 in the human promyelocytic cell line NB4. Leukemia, 1997, 11(12), 2131-2136. doi: 10.1038/sj.leu.2400855 PMID: 9447831
  34. Bergmann, C.L.M.S.; Pochmann, D.; Bergmann, J.; Bocca, F.B.; Proença, I.; Marinho, J.; Mello, A.; Dani, C. The use of retinoic acid in association with microneedling in the treatment of epidermal melasma: Efficacy and oxidative stress parameters. Arch. Dermatol. Res., 2021, 313(8), 695-704. doi: 10.1007/s00403-020-02140-8 PMID: 32978675
  35. Hong, T.K.; Lee-Kim, Y.C. Effects of retinoic acid isomers on apoptosis and enzymatic antioxidant system in human breast cancer cells. Nutr. Res. Pract., 2009, 3(2), 77-83. doi: 10.4162/nrp.2009.3.2.77 PMID: 20016705
  36. Dong, S.; Liang, S.; Cheng, Z.; Zhang, X.; Luo, L.; Li, L.; Zhang, W.; Li, S.; Xu, Q.; Zhong, M.; Zhu, J.; Zhang, G.; Hu, S. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α,-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J. Exp. Clin. Cancer Res., 2022, 41(1), 15. doi: 10.1186/s13046-021-02229-6 PMID: 34998404
  37. Lou, Q.; Zhang, M.; Zhang, K.; Liu, X.; Zhang, Z.; Zhang, X.; Yang, Y.; Gao, Y. Arsenic exposure elevated ROS promotes energy metabolic reprogramming with enhanced AKT-dependent HK2 expression. Sci. Total Environ., 2022, 836, 155691. doi: 10.1016/j.scitotenv.2022.155691 PMID: 35525345
  38. Bi, S.; Tang, J.; Zhang, L.; Huang, L.; Chen, J.; Wang, Z.; Chen, D.; Du, L. Fine particulate matter reduces the pluripotency and proliferation of human embryonic stem cells through ROS induced AKT and ERK signaling pathway. Reprod. Toxicol., 2020, 96, 231-240. doi: 10.1016/j.reprotox.2020.07.010 PMID: 32745510
  39. Hao, Y.; Huang, Y.; Chen, J.; Li, J.; Yuan, Y.; Wang, M.; Han, L.; Xin, X.; Wang, H.; Lin, D.; Peng, F.; Yu, F.; Zheng, C.; Shen, C. Exopolysaccharide from Cryptococcus heimaeyensis S20 induces autophagic cell death in non-small cell lung cancer cells via ROS/p38 and ROS/ERK signalling. Cell Prolif., 2020, 53(8), e12869. doi: 10.1111/cpr.12869 PMID: 32597573
  40. Yang, J.; Li, H.; Zhang, C.; Zhou, Y. Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways. JCI Insight, 2022, 7(3), e145475. doi: 10.1172/jci.insight.145475 PMID: 35132967
  41. Hung, A.C.; Tsai, C.H.; Hou, M.F.; Chang, W.L.; Wang, C.H.; Lee, Y.C.; Ko, A.; Hu, S.C.S.; Chang, F.R.; Hsieh, P.W.; Yuan, S.S.F. The synthetic β-nitrostyrene derivative CYT-Rx20 induces breast cancer cell death and autophagy via ROS-mediated MEK/ERK pathway. Cancer Lett., 2016, 371(2), 251-261. doi: 10.1016/j.canlet.2015.11.035 PMID: 26683774
  42. Kwon, J.; Lee, S.R.; Yang, K.S.; Ahn, Y.; Kim, Y.J.; Stadtman, E.R.; Rhee, S.G. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc. Natl. Acad. Sci., 2004, 101(47), 16419-16424. doi: 10.1073/pnas.0407396101 PMID: 15534200
  43. Brennan, J.P.; Bardswell, S.C.; Burgoyne, J.R.; Fuller, W.; Schröder, E.; Wait, R.; Begum, S.; Kentish, J.C.; Eaton, P. Oxidant-induced activation of type I protein kinase A is mediated by RI subunit interprotein disulfide bond formation. J. Biol. Chem., 2006, 281(31), 21827-21836. doi: 10.1074/jbc.M603952200 PMID: 16754666
  44. Giorgi, C.; Agnoletto, C.; Baldini, C.; Bononi, A.; Bonora, M.; Marchi, S.; Missiroli, S.; Patergnani, S.; Poletti, F.; Rimessi, A.; Zavan, B.; Pinton, P. Redox control of protein kinase C: cell- and disease-specific aspects. Antioxid. Redox Signal., 2010, 13(7), 1051-1085. doi: 10.1089/ars.2009.2825 PMID: 20136499
  45. Wentworth, C.C.; Alam, A.; Jones, R.M.; Nusrat, A.; Neish, A.S. Enteric commensal bacteria induce extracellular signal-regulated kinase pathway signaling via formyl peptide receptor-dependent redox modulation of dual specific phosphatase 3. J. Biol. Chem., 2011, 286(44), 38448-38455. doi: 10.1074/jbc.M111.268938 PMID: 21921027

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2024 Bentham Science Publishers