Inhibitors of Na + /K + ATPase exhibit antitumor effects on multicellular tumor spheroids of hepatocellular carcinoma

Hepatocellular carcinoma (HCC), one of the most common malignant cancers worldwide, is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in patients with HCC. The multicellul...

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Bibliographic Details
Published in:Scientific reports 2020-03, Vol.10 (1), p.5318-5318, Article 5318
Main Authors: Song, Yeonhwa, Lee, Su-Yeon, Kim, Sanghwa, Choi, Inhee, Kim, Se-Hyuk, Shum, David, Heo, Jinyeong, Kim, A-Ram, Kim, Kang Mo, Seo, Haeng Ran
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antitumor activity
Carcinoma, Hepatocellular - pathology
Cell Cycle - drug effects
Cell Line, Tumor
Cell migration
Cell Proliferation - drug effects
Cell Survival - drug effects
Chemotherapy
Digoxin
Digoxin - pharmacology
Drug Resistance, Neoplasm - drug effects
Drug screening
Drug Screening Assays, Antitumor - methods
Epithelial-Mesenchymal Transition - drug effects
Hepatocellular carcinoma
High-throughput screening
Humans
Liver cancer
Liver Neoplasms - pathology
Mesenchyme
Microenvironments
Multicellular tumor spheroids
Na+/K+-exchanging ATPase
Ouabain
Ouabain - pharmacology
Proof of Concept Study
Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors
Sodium-Potassium-Exchanging ATPase - metabolism
Spheroids
Spheroids, Cellular - drug effects
Tumor Microenvironment - drug effects
Tumor Microenvironment - physiology
Tumors
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Summary:Hepatocellular carcinoma (HCC), one of the most common malignant cancers worldwide, is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in patients with HCC. The multicellular tumor spheroid (MCTS) model is a powerful method for anticancer research because of its ability to mimic the complexity and heterogeneity of tumor tissue, the three-dimensional cellular context of tumor tissue, and the pathophysiological gradients of in vivo tumors. However, it is difficult to obtain meaningful results from the MCTS model without considering the conditions of clinical tumors. We, therefore, provided a proof of concept to determine whether spheroid models simulate in vivo tumor microenvironments. Through a high-throughput screening for HCC therapy using the MCTS model, we selected inhibitors of Na /K -ATPase (ouabain and digoxin) that could suppress cell growth and migration via inhibition of the epithelial-mesenchymal transition of HCC in vivo and in vitro. The results showed that this model provides a new paradigm for high-throughput drug screening and will significantly improve the efficiency of identifying new drugs for HCC treatment. Through utilization of MCTS models, here we found that inhibitors of Na /K -ATPase may be feasible as a novel target to sensitize HCC cells.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-62134-4