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Open Access 01-12-2023 | Glioblastoma | Research

Markedly divergent effects of Ouabain on a Temozolomide-resistant (T98G) vs. a Temozolomide-sensitive (LN229) Glioblastoma cell line

Authors: Heidrun Weidemann, Daniel Feger, Jan E. Ehlert, Marcus M. Menger, Robert C. Krempien

Published in: Discover Oncology | Issue 1/2023

Abstract

Background

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis. GMB are highly recurrent mainly because of radio- and chemoresistance. Radiotherapy with Temozolomide (TMZ) is until today the golden standard adjuvant therapy, however, the optimal treatment of recurrent glioblastoma remains controversial. Ouabain belongs to the Cardiotonic Steroids (CTS) the natural ligands of the Na/K-ATPase (NKA). It is established that the NKA represents a signal transducer with either stimulating or inhibiting cell growth, apoptosis, migration and angiogenesis. Over the last decade evidence grew that CTS have anti-tumor properties especially in GBM.

Aim

Proceeding from recent studies we wanted to further demonstrate a divergent effect of Ouabain on a TMZ-resistant (T98G) as compared to a TMZ-sensitive (LN229) GBM cell line.

Methods

We analyzed the effect of Ouabain on cell migration and plasma cell membrane potential (PCMP) in the LN229 and T98G GBM cell line as well as underlying mechanisms (Bcl-2 and p-Akt/pan-Akt expression). Moreover, we analyzed the anti-angiogenic effect of Ouabain on human umbilical vein endothelial cells (HUVECs).

Results

T98G cells showed a significant inhibition of cell migration and a significant depolarization of the PCMP at similar Ouabain concentrations (IC50 = 1.67 × 10^–7 M) resp. (IC50 = 2.72 × 10^–7 M) with a strong inverse correlation (R² = 0.95). In contrast, LN229 cells did not respond to Ouabain in these assays at all. Similarly, only T98G but not LN229 cells revealed Bcl-2 down-regulation at nanomolar Ouabain concentrations. This unique response to Ouabain is associated with a down-regulation of pan-Akt in T98G cells 24 h after Ouabain (1.0 × 10^–6 M) treatment. For the first time, the anti-angiogenic effect of Ouabain on HUVEC cells (IC50 = 5.49 × 10^–8 M) was demonstrated which correlated strongly with the anti-migratory effect (R² = 0.85).

Conclusion

The TMZ-resistant T98G cell line as compared to the TMZ-sensitive LN229 cell line shows a high sensitivity towards Ouabain. We consider it as a promising new compound especially in recurrent GBM to overcome the resistance to TMZ and irradiation.

Albesiano E, Han JE, Lim M. Mechanisms of local immunoresistance in glioma. Neurosurg Clin N Am. 2010;21(1):17–29. https://doi.org/10.1016/j.nec.2009.08.008.CrossRefPubMed

Le Rhun E, Rhun EL, Taillibert S, Chamberlain MC. The future of high-grade glioma: where we are and where are we going. Surg Neurol Int. 2015;6(Suppl 1):S9–44. https://doi.org/10.4103/2152-7806.151331.CrossRefPubMedPubMedCentral

Gately L, McLachlan SA, Dowling A, Philip J. Life beyond a diagnosis of glioblastoma: a systematic review of the literature. J Cancer Surviv. 2017;11(4):447–52. https://doi.org/10.1007/s11764-017-0602-7.CrossRefPubMed

Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30(9):907–11. https://doi.org/10.1212/wnl.30.9.907.CrossRefPubMed

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60. https://doi.org/10.1038/nature05236.CrossRefPubMed

Chargari C, Moncharmont C, Levy A, Guy JB, Bertrand G, Guilbert M, et al. Cancer stem cells, cornerstone of radioresistance and perspectives for radiosensitization: glioblastoma as an example. Bull Cancer. 2012;99(12):1153–60. https://doi.org/10.1684/bdc.2012.1666.CrossRefPubMed

Peitzsch C, Perrin R, Hill RP, Dubrovska A, Kurth I. Hypoxia as a biomarker for radioresistant cancer stem cells. Int J Radiat Biol. 2014;90(8):636–52. https://doi.org/10.3109/09553002.2014.916841.CrossRefPubMed

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. https://doi.org/10.1056/NEJMoa043330.CrossRefPubMed

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7.CrossRefPubMed

10.

Hasselbalch B, Lassen U, Hansen S, Holmberg M, Sorensen M, Kosteljanetz M, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol. 2010;12(5):508–16. https://doi.org/10.1093/neuonc/nop063.CrossRefPubMedPubMedCentral

11.

Jiang P, Mukthavaram R, Chao Y, Bharati IS, Fogal V, Pastorino S, et al. Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs. J Transl Med. 2014;12:13. https://doi.org/10.1186/1479-5876-12-13.CrossRefPubMedPubMedCentral

12.

Olson JJ, Nayak L, Ormond DR, Wen PY, Kalkanis SN, Committee ACJG. The role of cytotoxic chemotherapy in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2014;118(3):501–55. https://doi.org/10.1007/s11060-013-1338-5.CrossRefPubMed

13.

Martinho O, Silva-Oliveira R, Miranda-Goncalves V, Clara C, Almeida JR, Carvalho AL, et al. In vitro and in vivo analysis of RTK inhibitor efficacy and identification of its novel targets in glioblastomas. Transl Oncol. 2013;6(2):187–96. https://doi.org/10.1593/tlo.12400.CrossRefPubMedPubMedCentral

14.

Padfield E, Ellis HP, Kurian KM. Current therapeutic advances targeting EGFR and EGFRvIII in Glioblastoma. Front Oncol. 2015;5:5. https://doi.org/10.3389/fonc.2015.00005.CrossRefPubMedPubMedCentral

15.

Wachsberger PR, Lawrence YR, Liu Y, Daroczi B, Xu X, Dicker AP. Epidermal growth factor receptor expression modulates antitumor efficacy of vandetanib or cediranib combined with radiotherapy in human glioblastoma xenografts. Int J Radiat Oncol Biol Phys. 2012;82(1):483–91. https://doi.org/10.1016/j.ijrobp.2010.09.019.CrossRefPubMed

16.

Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: analysis of single-agent and combined modality approaches. Radiat Oncol. 2011;6:2. https://doi.org/10.1186/1748-717X-6-2.CrossRefPubMedPubMedCentral

17.

Lu-Emerson C, Duda DG, Emblem KE, Taylor JW, Gerstner ER, Loeffler JS, et al. Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol. 2015;33(10):1197–213. https://doi.org/10.1200/JCO.2014.55.9575.CrossRefPubMedPubMedCentral

18.

Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today. 2015;20(7):899–905. https://doi.org/10.1016/j.drudis.2015.02.011.CrossRefPubMed

19.

Sanati M, Binabaj MM, Ahmadi SS, Aminyavari S, Javid H, Mollazadeh H, et al. Recent advances in glioblastoma multiforme therapy: a focus on autophagy regulation. Biomed Pharmacother. 2022;155:113740. https://doi.org/10.1016/j.biopha.2022.113740.CrossRefPubMed

20.

Suryadevara CM, Verla T, Sanchez-Perez L, Reap EA, Choi BD, Fecci PE, et al. Immunotherapy for malignant glioma. Surg Neurol Int. 2015;6(Suppl 1):S68-77. https://doi.org/10.4103/2152-7806.151341.CrossRefPubMedPubMedCentral

21.

Chiarelli PA, Kievit FM, Zhang M, Ellenbogen RG. Bionanotechnology and the future of glioma. Surg Neurol Int. 2015;6(Suppl 1):S45-58. https://doi.org/10.4103/2152-7806.151334.CrossRefPubMedPubMedCentral

22.

Doris PA, Hayward-Lester A, Bourne D, Stocco DM. Ouabain production by cultured adrenal cells. Endocrinology. 1996;137(2):533–9. https://doi.org/10.1210/endo.137.2.8593799.CrossRefPubMed

23.

Hamlyn JM, Blaustein MP, Bova S, DuCharme DW, Harris DW, Mandel F, et al. Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci U S A. 1991;88(14):6259–63. https://doi.org/10.1073/pnas.88.14.6259.CrossRefPubMedPubMedCentral

24.

Hamlyn JM, Lu ZR, Manunta P, Ludens JH, Kimura K, Shah JR, et al. Observations on the nature, biosynthesis, secretion and significance of endogenous ouabain. Clin Exp Hypertens. 1998;20(5–6):523–33. https://doi.org/10.3109/10641969809053230.CrossRefPubMed

25.

Laredo J, Shah JR, Lu ZR, Hamilton BP, Hamlyn JM. Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenocortical cells via angiotensin type 2 receptors. Hypertension. 1997;29(1 Pt 2):401–7. https://doi.org/10.1161/01.hyp.29.1.401.CrossRefPubMed

26.

Sophocleous A, Elmatzoglou I, Souvatzoglou A. Circulating endogenous digitalis-like factor(s) (EDLF) in man is derived from the adrenals and its secretion is ACTH-dependent. J Endocrinol Invest. 2003;26(7):668–74. https://doi.org/10.1007/BF03347027.CrossRefPubMed

27.

Baecher S, Kroiss M, Fassnacht M, Vogeser M. No endogenous ouabain is detectable in human plasma by ultra-sensitive UPLC-MS/MS. Clin Chim Acta. 2014;431:87–92. https://doi.org/10.1016/j.cca.2014.01.038.CrossRefPubMed

28.

Lewis LK, Yandle TG, Hilton PJ, Jensen BP, Begg EJ, Nicholls MG. Endogenous ouabain is not ouabain. Hypertension. 2014;64(4):680–3. https://doi.org/10.1161/HYPERTENSIONAHA.114.03919.CrossRefPubMed

29.

Kiani Z, Shafiei M, Rahimi-Moghaddam P, Karkhane AA, Ebrahimi SA. In vitro selection and characterization of deoxyribonucleic acid aptamers for digoxin. Anal Chim Acta. 2012;748:67–72. https://doi.org/10.1016/j.aca.2012.08.025.CrossRefPubMed

30.

Pfeiffer F, Mayer G. Selection and biosensor application of aptamers for small molecules. Front Chem. 2016;4:25. https://doi.org/10.3389/fchem.2016.00025.CrossRefPubMedPubMedCentral

31.

Tokhtaeva E, Clifford RJ, Kaplan JH, Sachs G, Vagin O. Subunit isoform selectivity in assembly of Na K-ATPase alpha-beta heterodimers. J Biol Chem. 2012;287(31):26115–25. https://doi.org/10.1074/jbc.M112.370734.CrossRefPubMedPubMedCentral

32.

Mobasheri A, Fox R, Evans I, Cullingham F, Martin-Vasallo P, Foster CS. Epithelial Na, K-ATPase expression is down-regulated in canine prostate cancer; a possible consequence of metabolic transformation in the process of prostate malignancy. Cancer Cell Int. 2003;3(1):8. https://doi.org/10.1186/1475-2867-3-8.CrossRefPubMedPubMedCentral

33.

Sakai H, Suzuki T, Maeda M, Takahashi Y, Horikawa N, Minamimura T, et al. Up-regulation of Na(+), K(+)-ATPase alpha 3-isoform and down-regulation of the alpha1-isoform in human colorectal cancer. FEBS Lett. 2004;563(1–3):151–4. https://doi.org/10.1016/S0014-5793(04)00292-3.CrossRefPubMed

34.

Shibuya K, Fukuoka J, Fujii T, Shimoda E, Shimizu T, Sakai H, et al. Increase in ouabain-sensitive K+-ATPase activity in hepatocellular carcinoma by overexpression of Na+, K+-ATPase alpha 3-isoform. Eur J Pharmacol. 2010;638(1–3):42–6. https://doi.org/10.1016/j.ejphar.2010.04.029.CrossRefPubMed

35.

Newman RA, Yang P, Pawlus AD, Block KI. Cardiac glycosides as novel cancer therapeutic agents. Mol Interv. 2008;8(1):36–49. https://doi.org/10.1124/mi.8.1.8.CrossRefPubMed

36.

Aizman O, Aperia A. Na, K-ATPase as a signal transducer. Ann N Y Acad Sci. 2003;986:489–96. https://doi.org/10.1111/j.1749-6632.2003.tb07233.x.CrossRefPubMed

37.

Haas M, Wang H, Tian J, Xie Z. Src-mediated inter-receptor cross-talk between the Na+/K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J Biol Chem. 2002;277(21):18694–702. https://doi.org/10.1074/jbc.M111357200.CrossRefPubMed

38.

Xie Z. Ouabain interaction with cardiac Na/K-ATPase reveals that the enzyme can act as a pump and as a signal transducer. Cell Mol Biol (Noisy-le-grand). 2001;47(2):383–90.PubMed

39.

Shiratori O. Growth inhibitory effect of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. Gan. 1967;58(6):521–8.PubMed

40.

Al-Ghoul M, Valdes R Jr. Mammalian cardenolides in cancer prevention and therapeutics. Ther Drug Monit. 2008;30(2):234–8. https://doi.org/10.1097/FTD.0b013e31816b90ff.CrossRefPubMed

41.

Chen JQ, Contreras RG, Wang R, Fernandez SV, Shoshani L, Russo IH, et al. Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs? Breast Cancer Res Treat. 2006;96(1):1–15. https://doi.org/10.1007/s10549-005-9053-3.CrossRefPubMed

42.

Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses. 1999;53(6):543–8. https://doi.org/10.1054/mehy.1999.0985.CrossRefPubMed

43.

Lopez-Lazaro M. Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved. Expert Opin Ther Targets. 2007;11(8):1043–53. https://doi.org/10.1517/14728222.11.8.1043.CrossRefPubMed

44.

Badr CE, Wurdinger T, Tannous BA. Functional drug screening assay reveals potential glioma therapeutics. Assay Drug Dev Technol. 2011;9(3):281–9. https://doi.org/10.1089/adt.2010.0324.CrossRefPubMedPubMedCentral

45.

Denicolai E, Baeza-Kallee N, Tchoghandjian A, Carre M, Colin C, Jiglaire CJ, et al. Proscillaridin A is cytotoxic for glioblastoma cell lines and controls tumor xenograft growth in vivo. Oncotarget. 2014;5(21):10934–48. https://doi.org/10.18632/oncotarget.2541.CrossRefPubMedPubMedCentral

46.

Chen D, Song M, Mohamad O, Yu SP. Inhibition of Na+/K+-ATPase induces hybrid cell death and enhanced sensitivity to chemotherapy in human glioblastoma cells. BMC Cancer. 2014;14:716. https://doi.org/10.1186/1471-2407-14-716.CrossRefPubMedPubMedCentral

47.

Yang XS, Xu ZW, Yi TL, Xu RC, Li J, Zhang WB, et al. Ouabain suppresses the growth and migration abilities of glioma U87MG cells through inhibiting the Akt/mTOR signaling pathway and downregulating the expression of HIF1alpha. Mol Med Rep. 2018;17(4):5595–600. https://doi.org/10.3892/mmr.2018.8587.CrossRefPubMedPubMedCentral

48.

Lefranc F, Kiss R. The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas. Neoplasia. 2008;10(3):198–206. https://doi.org/10.1593/neo.07928.CrossRefPubMedPubMedCentral

49.

Menger L, Vacchelli E, Kepp O, Eggermont A, Tartour E, Zitvogel L, et al. Trial watch: Cardiac glycosides and cancer therapy. Oncoimmunology. 2013;2(2):23082. https://doi.org/10.4161/onci.23082.CrossRef

50.

Taylor MA, Das BC, Ray SK. Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma. Apoptosis. 2018;23(11–12):563–75. https://doi.org/10.1007/s10495-018-1480-9.CrossRefPubMedPubMedCentral

51.

Goldberger ZD, Goldberger AL. Therapeutic ranges of serum digoxin concentrations in patients with heart failure. Am J Cardiol. 2012;109(12):1818–21. https://doi.org/10.1016/j.amjcard.2012.02.028.CrossRefPubMedPubMedCentral

52.

Trenti A, Zulato E, Pasqualini L, Indraccolo S, Bolego C, Trevisi L. Therapeutic concentrations of digitoxin inhibit endothelial focal adhesion kinase and angiogenesis induced by different growth factors. Br J Pharmacol. 2017;174(18):3094–106. https://doi.org/10.1111/bph.13944.CrossRefPubMedPubMedCentral

53.

Harwood S, Little JA, Gallacher G, Perrett D, Edwards R, Dawnay A. Development of enzyme immunoassay for endogenous ouabain-like compound in human plasma. Clin Chem. 1997;43(5):715–22.CrossRefPubMed

54.

Lopatin DA, Ailamazian EK, Dmitrieva RI, Shpen VM, Fedorova OV, Doris PA, et al. Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. J Hypertens. 1999;17(8):1179–87. https://doi.org/10.1097/00004872-199917080-00018.CrossRefPubMed

55.

Manunta P, Stella P, Rivera R, Ciurlino D, Cusi D, Ferrandi M, et al. Left ventricular mass, stroke volume, and ouabain-like factor in essential hypertension. Hypertension. 1999;34(3):450–6. https://doi.org/10.1161/01.hyp.34.3.450.CrossRefPubMed

56.

Weidemann H. “The Lower Threshold” phenomenon in tumor cells toward endogenous digitalis-like compounds: Responsible for tumorigenesis? J Carcinog. 2012;11:2. https://doi.org/10.4103/1477-3163.92999.CrossRefPubMedPubMedCentral

57.

Litan A, Langhans SA. Cancer as a channelopathy: ion channels and pumps in tumor development and progression. Front Cell Neurosci. 2015;9:86. https://doi.org/10.3389/fncel.2015.00086.CrossRefPubMedPubMedCentral

58.

Molenaar RJ. Ion channels in glioblastoma. ISRN Neurol. 2011;2011:590249. https://doi.org/10.5402/2011/590249.CrossRefPubMedPubMedCentral

59.

Wang L, Zhou P, Craig RW, Lu L. Protection from cell death by mcl-1 is mediated by membrane hyperpolarization induced by K(+) channel activation. J Membr Biol. 1999;172(2):113–20. https://doi.org/10.1007/s002329900589.CrossRefPubMed

60.

Chittajallu R, Chen Y, Wang H, Yuan X, Ghiani CA, Heckman T, et al. Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G1/S phase progression of the cell cycle. Proc Natl Acad Sci U S A. 2002;99(4):2350–5. https://doi.org/10.1073/pnas.042698399.CrossRefPubMedPubMedCentral

61.

Gilbert MS, Saad AH, Rupnow BA, Knox SJ. Association of BCL-2 with membrane hyperpolarization and radioresistance. J Cell Physiol. 1996;168(1):114–22. https://doi.org/10.1002/(SICI)1097-4652(199607)168:1%3c114::AID-JCP14%3e3.0.CO;2-7.CrossRefPubMed

62.

Gilbert M, Knox S. Influence of Bcl-2 overexpression on Na+/K(+)-ATPase pump activity: correlation with radiation-induced programmed cell death. J Cell Physiol. 1997;171(3):299–304. https://doi.org/10.1002/(SICI)1097-4652(199706)171:3%3c299::AID-JCP8%3e3.0.CO;2-J.CrossRefPubMed

63.

Lauf PK, Alqahtani T, Flues K, Meller J, Adragna NC. Interaction between Na-K-ATPase and Bcl-2 proteins BclXL and Bak. Am J Physiol Cell Physiol. 2015;308(1):C51-60. https://doi.org/10.1152/ajpcell.00287.2014.CrossRefPubMed

64.

Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F, et al. SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther. 2008;7(5):1185–94. https://doi.org/10.1158/1535-7163.MCT-08-0126.CrossRefPubMedPubMedCentral

65.

Heiss M, Hellstrom M, Kalen M, May T, Weber H, Hecker M, et al. Endothelial cell spheroids as a versatile tool to study angiogenesis in vitro. FASEB J. 2015;29(7):3076–84. https://doi.org/10.1096/fj.14-267633.CrossRefPubMed

66.

Korff T, Augustin HG. Tensional forces in fibrillar extracellular matrices control directional capillary sprouting. J Cell Sci. 1999;112(Pt 19):3249–58.CrossRefPubMed

67.

Korff T, Augustin HG. Integration of endothelial cells in multicellular spheroids prevents apoptosis and induces differentiation. J Cell Biol. 1998;143(5):1341–52. https://doi.org/10.1083/jcb.143.5.1341.CrossRefPubMedPubMedCentral

68.

Joy AM, Beaudry CE, Tran NL, Ponce FA, Holz DR, Demuth T, et al. Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis. J Cell Sci. 2003;116(Pt 21):4409–17. https://doi.org/10.1242/jcs.00712.CrossRefPubMed

69.

Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol. 2005;23(10):2411–22. https://doi.org/10.1200/JCO.2005.03.089.CrossRefPubMed

70.

Suzuki-Karasaki Y, Suzuki-Karasaki M, Uchida M, Ochiai T. Depolarization controls TRAIL-sensitization and tumor-selective killing of cancer cells: crosstalk with ROS. Front Oncol. 2014;4:128. https://doi.org/10.3389/fonc.2014.00128.CrossRefPubMedPubMedCentral

71.

Bortner CD, Gomez-Angelats M, Cidlowski JA. Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis. J Biol Chem. 2001;276(6):4304–14. https://doi.org/10.1074/jbc.M005171200.CrossRefPubMed

72.

Hatok J, Racay P. Bcl-2 family proteins: master regulators of cell survival. Biomol Concepts. 2016;7(4):259–70. https://doi.org/10.1515/bmc-2016-0015.CrossRefPubMed

73.

Borner C, Martinou I, Mattmann C, Irmler M, Schaerer E, Martinou JC, et al. The protein bcl-2 alpha does not require membrane attachment, but two conserved domains to suppress apoptosis. J Cell Biol. 1994;126(4):1059–68. https://doi.org/10.1083/jcb.126.4.1059.CrossRefPubMed

74.

Schendel SL, Xie Z, Montal MO, Matsuyama S, Montal M, Reed JC. Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci U S A. 1997;94(10):5113–8. https://doi.org/10.1073/pnas.94.10.5113.CrossRefPubMedPubMedCentral

75.

Chanvorachote P, Pongrakhananon V. Ouabain downregulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis. Am J Physiol Cell Physiol. 2013;304(3):C263–72. https://doi.org/10.1152/ajpcell.00225.2012.CrossRefPubMed

76.

Fouque A, Lepvrier E, Debure L, Gouriou Y, Malleter M, Delcroix V, et al. The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria. Cell Death Differ. 2016;23(10):1702–16. https://doi.org/10.1038/cdd.2016.61.CrossRefPubMedPubMedCentral

77.

Koehler BC, Scherr AL, Lorenz S, Urbanik T, Kautz N, Elssner C, et al. Beyond cell death - antiapoptotic Bcl-2 proteins regulate migration and invasion of colorectal cancer cells in vitro. PLoS ONE. 2013;8(10):76446. https://doi.org/10.1371/journal.pone.0076446.CrossRef

78.

Um HD. Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species. Oncotarget. 2016;7(5):5193–203. https://doi.org/10.18632/oncotarget.6405.CrossRefPubMed

79.

Gao J, Wymore RS, Wang Y, Gaudette GR, Krukenkamp IB, Cohen IS, et al. Isoform-specific stimulation of cardiac Na/K pumps by nanomolar concentrations of glycosides. J Gen Physiol. 2002;119(4):297–312. https://doi.org/10.1085/jgp.20028501.CrossRefPubMedPubMedCentral

80.

You I, Erickson EC, Donovan KA, Eleuteri NA, Fischer ES, Gray NS, et al. Discovery of an AKT degrader with prolonged inhibition of downstream signaling. Cell Chem Biol. 2020;27(1):66-73 e7. https://doi.org/10.1016/j.chembiol.2019.11.014.CrossRefPubMed

81.

Liu J, Shapiro JI. Regulation of sodium pump endocytosis by cardiotonic steroids: molecular mechanisms and physiological implications. Pathophysiology. 2007;14(3–4):171–81. https://doi.org/10.1016/j.pathophys.2007.09.008.CrossRefPubMed

82.

Rosen H, Glukhman V, Feldmann T, Fridman E, Lichtstein D. Cardiac steroids induce changes in recycling of the plasma membrane in human NT2 cells. Mol Biol Cell. 2004;15(3):1044–54. https://doi.org/10.1091/mbc.e03-06-0391.CrossRefPubMedPubMedCentral

83.

Hafner S, Schmiech M, Lang SJ. The cardenolide glycoside acovenoside a interferes with epidermal growth factor receptor trafficking in non-small cell lung cancer cells. Front Pharmacol. 2021;12:611657. https://doi.org/10.3389/fphar.2021.611657.CrossRefPubMedPubMedCentral

84.

Cota CD, Dreier MS, Colgan W, Cha A, Sia T, Davidson B. Cyclin-dependent Kinase 1 and Aurora Kinase choreograph mitotic storage and redistribution of a growth factor receptor. PLoS Biol. 2021;19(1):3001029. https://doi.org/10.1371/journal.pbio.3001029.CrossRef

85.

Szymonowicz K, Oeck S, Malewicz NM, Jendrossek V. New insights into protein kinase B/Akt signaling: role of localized Akt activation and compartment-specific target proteins for the cellular radiation response. Cancers (Basel). 2018. https://doi.org/10.3390/cancers10030078.CrossRefPubMed

86.

Kometiani P, Liu L, Askari A. Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol Pharmacol. 2005;67(3):929–36. https://doi.org/10.1124/mol.104.007302.CrossRefPubMed

87.

Mijatovic T, Op De Beeck A, Van Quaquebeke E, Dewelle J, Darro F, de Launoit Y, et al. The cardenolide UNBS1450 is able to deactivate nuclear factor kappaB-mediated cytoprotective effects in human non-small cell lung cancer cells. Mol Cancer Ther. 2006;5(2):391–9. https://doi.org/10.1158/1535-7163.MCT-05-0367.CrossRefPubMed

88.

Xiao Y, Meng C, Lin J, Huang C, Zhang X, Long Y, et al. Ouabain targets the Na(+)/K(+)-ATPase alpha3 isoform to inhibit cancer cell proliferation and induce apoptosis. Oncol Lett. 2017;14(6):6678–84. https://doi.org/10.3892/ol.2017.7070.CrossRefPubMedPubMedCentral

89.

Ahir BK, Engelhard HH, Lakka SS. Tumor development and angiogenesis in adult brain tumor: glioblastoma. Mol Neurobiol. 2020;57(5):2461–78. https://doi.org/10.1007/s12035-020-01892-8.CrossRefPubMedPubMedCentral

90.

Mosteiro A, Pedrosa L, Ferres A, Diao D, Sierra A, Gonzalez JJ. The vascular microenvironment in glioblastoma: a comprehensive review. Biomedicines. 2022. https://doi.org/10.3390/biomedicines10061285.CrossRefPubMedPubMedCentral

91.

Zhang M, Ye G, Li J, Wang Y. Recent advance in molecular angiogenesis in glioblastoma: the challenge and hope for anti-angiogenic therapy. Brain Tumor Pathol. 2015;32(4):229–36. https://doi.org/10.1007/s10014-015-0233-5.CrossRefPubMed

92.

Kim MM, Umemura Y, Leung D. Bevacizumab and glioblastoma: past, present, and future directions. Cancer J. 2018;24(4):180–6. https://doi.org/10.1097/PPO.0000000000000326.CrossRefPubMed

93.

Zhang T, Xin Q, Kang JM. Bevacizumab for recurrent glioblastoma: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(21):6480–91. https://doi.org/10.26355/eurrev_202111_27092.CrossRefPubMed

94.

Nagaoka K, Kurauchi Y, Asano D, Morita A, Sakamoto K, Nakahara T. Pharmacological inhibition of Na(+)/K(+)-ATPase induces neurovascular degeneration and glial cell alteration in the rat retina. Exp Eye Res. 2022;220:109107. https://doi.org/10.1016/j.exer.2022.109107.CrossRefPubMed

95.

Zhao GH, Qiu YQ, Yang CW, Chen IS, Chen CY, Lee SJ. The cardenolides ouabain and reevesioside A promote FGF2 secretion and subsequent FGFR1 phosphorylation via converged ERK1/2 activation. Biochem Pharmacol. 2020;172:113741. https://doi.org/10.1016/j.bcp.2019.113741.CrossRefPubMed

96.

Jansson-Lofmark R, Hjorth S, Gabrielsson J. Does in vitro potency predict clinically efficacious concentrations? Clin Pharmacol Ther. 2020;108(2):298–305. https://doi.org/10.1002/cpt.1846.CrossRefPubMedPubMedCentral

97.

Poole-Wilson PA, Galindez E, Fry CH. Effect of ouabain in therapeutic concentrations on K+ exchange and contraction of human and rabbit myocardium. Clin Sci (Lond). 1979;57(5):415–20. https://doi.org/10.1042/cs0570415.CrossRefPubMed

98.

Cao H, Li X, Wang F, Zhang Y, Xiong Y, Yang Q. Phytochemical-mediated glioma targeted treatment: drug resistance and novel delivery systems. Curr Med Chem. 2020;27(4):599–629. https://doi.org/10.2174/0929867326666190809221332.CrossRefPubMed

99.

Mohamadian M, Ahmadi SS, Bahrami A, Ferns GA. Review on the therapeutic potential of curcumin and its derivatives on glioma biology. Neurochem Res. 2022;47(10):2936–53. https://doi.org/10.1007/s11064-022-03666-1.CrossRefPubMed

100.

Qoorchi Moheb Seraj F, Heravi-Faz N, Soltani A, Ahmadi SS, Shahbeiki F, Talebpour A, et al. Thymol has anticancer effects in U-87 human malignant glioblastoma cells. Mol Biol Rep. 2022;49(10):9623–32. https://doi.org/10.1007/s11033-022-07867-3.CrossRefPubMed

101.

Sanati M, Afshari AR, Kesharwani P, Sukhorukov VN, Sahebkar A. Recent trends in the application of nanoparticles in cancer therapy: the involvement of oxidative stress. J Control Release. 2022;348:287–304. https://doi.org/10.1016/j.jconrel.2022.05.035.CrossRefPubMed

Title: Markedly divergent effects of Ouabain on a Temozolomide-resistant (T98G) vs. a Temozolomide-sensitive (LN229) Glioblastoma cell line
Authors: Heidrun Weidemann
Daniel Feger
Jan E. Ehlert
Marcus M. Menger
Robert C. Krempien
Publication date: 01-12-2023
Publisher: Springer US
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Published in: Discover Oncology / Issue 1/2023
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-023-00633-2

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Obesity Clinical Trial Summary

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A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

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