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Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translational Medicine TRIM)ORCID iD: 0000-0003-2462-0178
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translational Medicine TRIM)ORCID iD: 0000-0001-8962-0860
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translational Medicine TRIM)ORCID iD: 0000-0003-0943-7797
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 15, p. 1-14, article id 8237Article in journal (Refereed) Published
Abstract [en]

Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.

Place, publisher, year, edition, pages
MDPI, 2022. Vol. 23, no 15, p. 1-14, article id 8237
Keywords [en]
pancreatic cancer, digitoxin, cardiac glycosides, PDAC, KRAS, metabolism, ROS, cell proliferation
National Category
Medical and Health Sciences Clinical Laboratory Medicine
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-21727DOI: 10.3390/ijms23158237ISI: 000839229300001PubMedID: 35897809Scopus ID: 2-s2.0-85137100614OAI: oai:DiVA.org:his-21727DiVA, id: diva2:1690264
Note

CC BY 4.0

Correspondence: ferenc.szekeres@his.se

Funding: This research was funded by Assar Gabrielsson Foundation, grant FB19-80.

Available from: 2022-08-25 Created: 2022-08-25 Last updated: 2023-04-27Bibliographically approved
In thesis
1. Repurposing digitoxin in the treatment of pancreatic ductal adenocarcinoma: genotypic and phenotypic features as biomarkers for digitoxin sensitivity in vitro
Open this publication in new window or tab >>Repurposing digitoxin in the treatment of pancreatic ductal adenocarcinoma: genotypic and phenotypic features as biomarkers for digitoxin sensitivity in vitro
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide. The dismal prognosis and lack of effective treatments urges for increased research efforts in developing new treatment regimens. Since the development of new cancer treatments are expensive and time consuming, repurposing drugs is preferable when possible. This strategy will also be of great value for people in low income countries, to increase the availability of effective cancer treatments to affordable costs. Digitoxin, a cardiac glycoside, has been shown to have anti-cancer effects. It binds to the α subunit of the Na+/K+-ATPase, leading to increased concentrations of intracellular calcium and eventually cell death. There seems also to be other mechanisms elicited in cancer cells by digitoxin. The α subunit occurs in three isoforms, of which α3 has the highest affinity to digitoxin and frequently found over-expressed in tumor cells compared to normal cells.

PDAC cancer cells, both cell lines and tumors, differ in their genotype and in the metabolic subtype, proliferation rate and inflammatory status. To be able to individualize treatment regimens it is important to be aware of the specific vulnerabilities (genotypic or phenotypic characteristics increasing the sensitivity to digitoxin) of each PDAC tumor/cell line. This research aims to investigate the potential of using digitoxin as an anti-cancer treatment in PDAC, and analyze its effects on cell viability, metabolism and inflammatory status in PDAC cell lines in vitro with the goal to find biomarkers for digitoxin sensitivity.

The analyses of the effects of digitoxin was performed in five cell lines derived from PDAC tumors, either from primary tumors or metastases. Cell lines derived from PDAC are sensitive to digitoxin treatment to different degrees. High expression of α3 seems to be indicative for digitoxin sensitivity, as do a high proliferation rate seen in cell lines derived from primary tumors. Both subunit expression and proliferation rate should be further evaluated in PDAC tumors to confirm their potential to be used as biomarkers clinically.

In the hunt for the working mechanism behind the anti-cancer effects of digitoxin, the choline pathway, a pathway commonly affected in tumors was enlightened in the metabolomics study, affected in all five cell lines tested. Choline metabolites are important for maintaining the cell membrane and are involved in energy metabolism using lipids. Digitoxin induced an up-regulation of choline and glycerophosphocholine, which rendered us to propose a novel theory about possible interactions between two functional complexes in the cell membrane, the Na+/K+-ATPase/EGFR/c-Src and the EGFR/c-Src – Chkα. The hypothesis is that when digitoxin binds to the Na+/K+-ATPase it leads to inactivation of Chkα with a subsequent decrease in the synthesis of phosphocholine and phosphatidylcholine. Since cancer cells rely on abundance of choline metabolites, we believe an inhibition of this pathway to be deleterious for these cells.

Finally, we conclude that digitoxin has great potential as an anti-cancer treatment for some patients with pancreatic ductal adenocarcinoma. To optimize treatment results, a thorough investigation of the tumor genotype and phenotype must be done for each patient. To further increase treatment success, combination of digitoxin with other treatments for synergistic effects could be beneficial. 

Place, publisher, year, edition, pages
Jönköping: Jönköping University, School of Health and Welfare, 2023. p. 107
Series
Dissertation Series. School of Health and Welfare, ISSN 1654-3602 ; 124
Keywords
pancreatic ductal adenocarcinoma, Na+/K+-ATPase, digitoxin, cardiac glycoside, metabolomics, choline
National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-22470 (URN)978-91-88669-23-0 (ISBN)978-91-88669-24-7 (ISBN)
Public defence
2023-05-12, G110, University of Skövde, Skövde, 13:00 (Swedish)
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Supervisors
Note

"This thesis is based on research conducted at the University of Skövde during the enrollment as a PhD-student at the School of Health and Welfare at Jönköping University."

Två av fyra delarbeten (övriga se rubriken Delarbeten/List of papers):

Paper III

Lindholm H, Herring M, Faresjö M, Haux J, Szekeres F, Ejeskär K. Inflammasomes can be formed in pancreatic cancer cells, and NLRP3 inflammasome associated genes are up-regulated in primary pancreatic tumors. (Submitted)

Paper IV

Lindholm H, Ulfenborg B, Faresjö M, Haux J, Ejeskär K, Szekeres F. Digitoxin treatment affects choline metabolism in pancreatic cancer cells (Manuscript)

Available from: 2023-04-27 Created: 2023-04-27 Last updated: 2023-04-27Bibliographically approved

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Lindholm, HeléneEjeskär, KatarinaSzekeres, Ferenc

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