Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer

Lin, Sheng; Chang, Hsiu Hui; Lai, Yi Hua; Lin, Chung‐Sheng; Chen, Min Hsuan; Chang, Gee Chen; Tsai, Meng Feng; Chen, Jeremy J.W.

doi:10.1371/journal.pone.0123305

Cited by 57 publications

(58 citation statements)

References 45 publications

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“…Given our new data and the reported role of TGF-β in stroma development and metastasis [56–58], it is plausible that cardiac glycosides may have anti-cancer activity through downregulation of TGFβR2 in relevant cells. However, while multiple studies have demonstrated the anti-proliferative [24,59] and pro-apoptotic effects [60,61] of cardiac glycosides on various cancer cells in vitro , the effect of cardiac glycosides in the in vivo models of cancer has not been rigorously assessed.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

Reed

Chan

et al. 2016

PLoS ONE

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Transforming growth factor-beta (TGF-β) is a multi-functional cytokine implicated in the control of cell growth and differentiation. TGF-β signals through a complex of TGF-β receptors 1 and 2 (TGFβR1 and TGFβR2) that phosphorylate and activate Smad2/3 transcription factors driving transcription of the Smad-target genes. The Na+/K+-ATPase is an integral plasma membrane protein critical for maintaining the electro-chemical gradient of Na+ and K+ in the cell. We found that inhibition of the Na+/K+ ATPase by ouabain results in a dramatic decrease in the expression of TGFβR2 in human lung fibrobalsts (HLF) at the mRNA and protein levels. This was accompanied by inhibition of TGF-β-induced Smad phosphorylation and the expression of TGF-β target genes, such as fibronectin and smooth muscle alpha-actin. Inhibition of Na+/K+ ATPase by an alternative approach (removal of extracellular potassium) had a similar effect in HLF. Finally, treatment of lung alveolar epithelial cells (A549) with ouabain also resulted in the downregulation of TGFβR2, the inhibition of TGF-β-induced Smad phosphorylation and of the expression of mesenchymal markers, vimentin and fibronectin. Together, these data demonstrate a critical role of Na+/K+-ATPase in the control of TGFβR2 expression, TGF-β signaling and cell responses to TGF-β.

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Section: Discussionmentioning

confidence: 99%

Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

Reed

Chan

et al. 2016

PLoS ONE

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“…The detailed procedures of colony formation assay were described previously [34]. Briefly, 500 cells were resuspended in culture medium and seeded in six-well plates.…”

Section: Methodsmentioning

confidence: 99%

Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

Wang

Peng

et al. 2016

Oncotarget

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AimDespite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely used antidiabetic agent, may reverse crizotinib resistance through inhibition of IGF-1R signaling.ResultsThe present study revealed that metformin effectively increased the sensitivity of both crizotinib-sensitive and -resistant non-small cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in crizotinib-resistant cells. Furthermore, the addition of IGF-1 to crizotinib-sensitive H2228 cells induced crizotinib resistance, which was overcome by metformin.Experimental designThe effects of metformin to reverse crizotinib resistance were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 incorporation assay, flow cytometry analysis, Western blot analysis, and colony-forming assay.ConclusionsMetformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival.

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“…14 Itraconazole (an antifungal drug), 15,16 nelfinavir (a competitive inhibitor of the human immunodeficiency virus aspartyl protease), 17 and digoxin (a cardiac glycoside) are some of the drugs that have been explored for their anticancer properties. 18 The repurposed drugs, such as nelfinavir and digoxin, are under investigation in combination with other chemotherapeutic candidates for pancreatic cancer. 19 In the current study, we set out to identify ERK/MAPK pathway-targeting inhibitors from a set of existing drugs for possible targeted therapeutics of gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients

Pandian

Panneerpandian

Devanandan

et al. 2020

Annals of the New York Academy of Sciences

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The identification of new drugs for the targeted therapy of gastric cancer remains an important need. The RAS/RAF/MEK/ERK/ELK1 signaling cascade is activated in many cancers, including gastric cancer. To identify the targetable inhibitors of the ERK/MAPK pathway, we performed a repurposing screening of a panel of antimicrobial agents in gastric cancer cells using an ERK/MAPK-driven firefly luciferase reporter assay. Multiple antibiotics were identified to inhibit ERK-mediated transcriptional activity. Among them, doxycycline showed high inhibition of ERK/MAPK-regulated transcriptional activity and the levels of ERK proteins. Doxycycline was further identified to inhibit the proliferation and the colony-and spheroid-forming potential of gastric cancer cells. By in vitro signaling pathway and genome-wide expression profiling analyses, doxycycline was identified to inhibit signaling pathways and transcriptional activities regulated by ER, Myc, E2F1, Wnt, SMAD2/3/4, Notch, and OCT4. Doxycycline was also found to activate p53-, ATF6-, NRF1/2-, and MTF1-mediated transcription and inhibit the transcription of histones, proteasomal genes, fibroblast growth factor, and other oncogenic factors. These observations show the multitargeting and targeted therapeutic features of doxycycline for a subset of gastric tumors.

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Digoxin Suppresses Tumor Malignancy through Inhibiting Multiple Src-Related Signaling Pathways in Non-Small Cell Lung Cancer

Cited by 57 publications

References 45 publications

Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients

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