ArticleBiochemical pharmacology2014
Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation.
Article in Biochemical pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Anoikis: To Die or Not to Die?International journal of molecular sciences · 2026Review
- Metabolic reprogramming and signaling adaptations in anoikis resistance: mechanisms and therapeutic targets.Molecular and cellular biochemistry · 2025Review
- Cardiac glycoside ouabain efficiently targets leukemic stem cell apoptotic machinery independent of cell differentiation status.Cell communication and signaling : CCS · 2023Article
- Review
- Review
- Cardiac glycosides fromRSC advances · 2022Article
- Implications of Synthetic Modifications of the Cardiotonic Steroid Lactone Ring on Cytotoxicity.The Journal of membrane biology · 2021Article
- Potential antitumor activity of digitoxin and user-designed analog administered to human lung cancer cells.Biochimica et biophysica acta. General subjects · 2020Article
- Antitumor Activity of the Cardiac Glycoside αlDiginoside by Modulating Mcl-1 in Human Oral Squamous Cell Carcinoma Cells.International journal of molecular sciences · 2020Article
- Cypripedin diminishes an epithelial-to-mesenchymal transition in non-small cell lung cancer cells through suppression of Akt/GSK-3β signalling.Scientific reports · 2018Article
- Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death.Frontiers in pharmacology · 2018Article
- Anticancer and Immunogenic Properties of Cardiac Glycosides.Molecules (Basel, Switzerland) · 2017Review
- Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy.Molecules (Basel, Switzerland) · 2017Review
- Cytotoxic effects of the cardenolide convallatoxin and its Na,K-ATPase regulation.Molecular and cellular biochemistry · 2017Article
- Autophagy-Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog.Journal of cellular physiology · 2016Article
- Influence of Sugar Amine Regiochemistry on Digitoxigenin Neoglycoside Anticancer Activity.ACS medicinal chemistry letters · 2015Article
- Analysis of proliferation and apoptotic induction by 20 steroid glycosides in 143B osteosarcoma cells in vitro.Cell proliferation · 2015Article
- Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450.Cell death & disease · 2015Article
- Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells.Biosensors & bioelectronics · 2014Article
- Cryptocaryol Structure-Activity Relationship Study of Cancer Cell Cytotoxicity and Ability to Stabilize PDCD4.ACS medicinal chemistry letters · 2014Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50=11.9 nM) than digitoxin (IC50=90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
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