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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Lu Li, Hui-Min Xi, Hao Lu and Xun Cai*

DOI: 10.2174/0118715206273000231211092743

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

Page: [412 - 422] Pages: 11

  • * (Excluding Mailing and Handling)

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.

Graphical Abstract

[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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1074/jbc.M111.268938] [PMID: 21921027]