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

Abstract

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.

Cardiac Glycosides as Immune System Modulators

“…Among such potential repurposed drug candidates belong, for example, cardiac glycosides (CGs), currently used in clinical practice for the treatment of heart diseases, such as congestive heart failure or cardiac arrhythmias. Furthermore, CGs also exert very promising anticancer activity both in vitro and in vivo [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], which is based mainly on the induction of complex signaling cascades in Na + /K + -ATPase (NKA) signalosome and induction of immune response. This fact could be utilized not only for cancer treatment but also in the treatment of a plethora of autoimmune and inflammatory diseases.…”

Anti-Cancer Effect of Moroccan Cobra Naja haje Venom and Its Fractions against Hepatocellular Carcinoma in 3D Cell Culture

“…Treatment options for HCC are divided into surgical resection of the tumor, and the treatment with the multi-kinase inhibitors such as sorafenib; however, it showed only partial clinical efficacy in patients with liver cancer [24,25]. Moreover, it was established that HCC rapidly becomes sorafenib-resistant [26]. To improve treatment options, the discovery of new drugs for HCC is necessary to improve the clinical treatment of those patients.…”

Research Progress of Locally Resonance Acoustic Metamaterials

“…The third-generation thin-film acoustic metamaterial structure was proposed in 2015. Metal electrode is introduced as an additional mass vibrator into locally resonance film [15][16]. Acoustic wave band is controlled by active phase modulation.…”