Cardiac Glycosides in Glioblastoma
From Na⁺/K⁺-ATPase Inhibition to Divergent Stress Pathways
DOI:
https://doi.org/10.58445/rars.4304Keywords:
Cardiac glycosides, Glioblastoma, ER stress responseAbstract
Cardiac glycosides, a class of steroid natural products historically used to treat heart failure, have re-emerged as candidate anticancer agents in glioblastoma (GBM), the most aggressive primary brain tumor in adults. All of them share one starting point: high-affinity binding to a conserved pocket on the Na⁺/K⁺-ATPase (NKA) ion pump, which blocks the pump's normal cation exchange cycle (Kanai et al., 2021; Laursen et al., 2015). This review traces what happens after that shared event and argues that the pathway then splits into two only partially overlapping downstream branches: an endoplasmic reticulum (ER) stress response driven through PERK–eIF2α–CHOP signaling, best documented for bufalin in glioma cell lines (Shen et al., 2014), and a suppression of hypoxia-inducible factor 1-alpha (HIF-1α), best documented for digoxin and digitoxin (Zhang et al., 2008; Lee et al., 2017). A complication runs through both branches: the same ER-stress response can trigger protective autophagy that delays rather than causes cell death, so the outcome may depend on a stress "threshold" that has not yet been quantified for any single glycoside in a single GBM line (Shen et al., 2014; Yan et al., 2015). Translating either branch into a usable GBM therapy is complicated by a real concentration gap: the doses shown to suppress HIF-1α or trigger ER stress in vitro generally exceed doses reached safely in humans, with digitoxin a partial exception (Lee et al., 2017; Kurzeder et al., 2025). The review closes by proposing molecular docking, using existing crystal structures of glycoside-bound NKA (PDB 7DDH, 4RET, 4RES) and the PERK kinase domain (PDB 3QD2), as a way to generate hypotheses about why different glycosides favor different branches, not to confirm them.
References
Berges R, Denicolai E, Tchoghandjian A, Baeza-Kallee N, Honore S, Figarella-Branger D, Braguer D. (2018). Proscillaridin A exerts anti-tumor effects through GSK3β activation and alteration of microtubule dynamics in glioblastoma. Cell Death & Disease, 9, 984. 10.1038/s41419-018-1018-7
Bou-Gharios J, Noël G, Burckel H. (2024). Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme. Cell Death & Disease, 15, 503. 10.1038/s41419-024-06904-2
Chovancova B, Liskova V, Babula P, Krizanova O. (2020). Role of Sodium/Calcium Exchangers in Tumors. Biomolecules, 10(9), 1257. 10.3390/biom10091257
Cui W, Li J, Ron D, Sha B. (2011). The structure of the PERK kinase domain suggests the mechanism for its activation. Acta Crystallographica Section D, 67, 423–428. 10.1107/S0907444911006445
Kanai R, Cornelius F, Ogawa H, Motoyama K, Vilsen B, Toyoshima C. (2021). Binding of cardiotonic steroids to Na+,K+-ATPase in the E2P state. PNAS, 118(1), e2020438118. 10.1073/pnas.2020438118
Khan I, Baig MH, Mahfooz S, et al. (2021). Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma. International Journal of Molecular Sciences, 22(3), 1318. 10.3390/ijms22031318
Kumavath R, Paul S, Pavithran H, et al. (2021). Emergence of Cardiac Glycosides as Potential Drugs: Current and Future Scope for Cancer Therapeutics. Biomolecules, 11(9), 1275. 10.3390/biom11091275
Kurzeder C, Nguyen-Sträuli BD, Krol I, et al. (2025). Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: a proof-of-concept trial. Nature Medicine, 31(4), 1120–1124. 10.1038/s41591-024-03486-6
Lan YL, et al. (2019). The sodium pump α1 subunit regulates bufalin sensitivity of human glioblastoma cells through the p53 signaling pathway. Cell Biology and Toxicology, 35, 521–539. 10.1007/s10565-019-09462-y
Laursen M, Gregersen JL, Yatime L, Nissen P, Fedosova NU. (2015). Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex. PNAS, 112(6), 1755–1760. 10.1073/pnas.1422997112
Lee DH, Oh SC, Giles AJ, Jung J, Gilbert MR, Park DM. (2017). Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells. Oncotarget, 8(25), 40233–40245. 10.18632/oncotarget.16714
Li X, Zheng J, Chen S, et al. (2021). Oleandrin, a cardiac glycoside, induces immunogenic cell death via the PERK/eIF2α/ATF4/CHOP pathway in breast cancer. Cell Death & Disease, 12(4), 314. 10.1038/s41419-021-03605-y
LingHu HR, Luo H, Gang L. (2020). Bufalin Induces Glioma Cell Death by Apoptosis or Necroptosis. OncoTargets and Therapy, 13, 4767–4778. 10.2147/OTT.S242567
Liu K, Tsung K, Attenello FJ. (2020). Characterizing Cell Stress and GRP78 in Glioma to Enhance Tumor Treatment. Frontiers in Oncology, 10, 608911. 10.3389/fonc.2020.608911
Miao Q, et al. (2013). Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells. International Journal of Molecular Sciences, 14(1), 1370–1382. 10.3390/ijms14011370
Mijatovic T, et al. (2013). Trial watch: Cardiac glycosides and cancer therapy. OncoImmunology. PMID 23525565. (Abstract-level source; full text not verified for this review.)
Pantsar T, Poso A. (2018). Binding Affinity via Docking: Fact and Fiction. Molecules, 23(8), 1899. 10.3390/molecules23081899
Pessôa MTC, Alves SLG, Taranto AG, Villar JAFP, Blanco G, Barbosa LA. (2018). Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 85–97. 10.1080/14756366.2017.1380637
Scranton K, John S, Angelini M, et al. (2025). The mechanism of action of digoxin requires the sodium-dependent inactivation of the sodium-calcium exchanger. Science Advances, 11(51). 10.1126/sciadv.ady9596
Shen S, Zhang Y, Wang Z, Zhang R, Gong X. (2014). Bufalin Induces the Interplay between Apoptosis and Autophagy in Glioma Cells through Endoplasmic Reticulum Stress. International Journal of Biological Sciences, 10(2), 212–224. 10.7150/ijbs.8056
Škubník J, Svobodová Pavlíčková V, Psotová J, Rimpelová S. (2021). Cardiac Glycosides as Autophagy Modulators. Cells, 10(12), 3341. 10.3390/cells10123341
Teng L, Hejazi S, et al. (2014). Systemic anticancer neural stem cells in combination with a cardiac glycoside for glioblastoma therapy. Stem Cells, 32(8), 2021–2032. (Abstract-level source; full text not verified for this review.)
Tokugawa M, et al. (2021). Periplocin and cardiac glycosides suppress the unfolded protein response. Scientific Reports, 11, 9528. 10.1038/s41598-021-89074-x
Valluri A, Lawrence L, Denning KL, Cuda J, Zhu GZ. (2022). Cardiac Glycosides Increase Temozolomide Anticancer Activity in Therapy Resistant Glioblastoma Cells. International Journal of Translational Medicine, 2(2), 148–155. 10.3390/ijtm2020012
Yan M-M, Ni J-D, Song D, Ding M, Huang J. (2015). Interplay between unfolded protein response and autophagy promotes tumor drug resistance. Oncology Letters, 10(4), 1959–1969. 10.3892/ol.2015.3508
Ye Q, Zhou X, Ren H, et al. (2023). An overview of the past decade of bufalin in the treatment of refractory and drug-resistant cancers. Frontiers in Pharmacology, 14, 1274336. 10.3389/fphar.2023.1274336
Zhang H, Qian DZ, Tan YS, et al. (Semenza GL, senior author). (2008). Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. PNAS, 105(50), 19579–19586. 10.1073/pnas.0809763105
Zhao H, Li Q, Pang J, Jin H, Li H, Yang X. (2017). Blocking autophagy enhances the pro-apoptotic effect of bufalin on human gastric cancer cells through endoplasmic reticulum stress. Biology Open, 6(10), 1416–1422. 10.1242/bio.026344
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