Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers.

Non-small cell lung cancers (NSCLCs) are the leading cause of cancer deaths in most developed countries. Targeting heat shock protein 70 (Hsp70) expression and function, together with the induction of lysosomal membrane permeabilization (LMP), could overcome the multiple anti-cell death mechanisms evidenced in NSCLCs that are responsible for the failure of currently used chemotherapeutic drugs. Because cardenolides bind to the sodium pump, they affect multiple signaling pathways and thus have a number of marked effects on tumor cell behavior. The aim of the present study was to characterize in vitro and in vivo the antitumor effects of a new cardenolide (UNBS1450) on experimental human NSCLCs. UNBS1450 is a potent source of in vivo antitumor activity in the case of paclitaxel-and oxaliplatin-resistant subcutaneous human NCI-H727 and orthotopic A549 xenografts in nude mice. In vitro UNBS1450-mediated antitumor activity results from the induction of nonapoptotic cell death. UNBS1450 mediates the decrease of Hsp70 at both mRNA and protein levels, and this is at least partly due to UNBS1450-induced downregulation of NFAT5/TonEBP (a factor responsible for the transcriptional control of Hsp70). These effects were paralleled by the induction of LMP, as evidenced by acridine orange staining and immunofluorescence analysis for cathepsin B accumulation.

• Publication year

  2006

• Venue

  Neoplasia

• Publication date

  2006-05-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1593/NEO.05850PMID 16790089PMCID PMC1592454
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The cardenolide UNBS1450 is able to deactivate nuclear factor κB–mediated cytoprotective effects in human non–small cell lung cancer cells

  2006cited by this paper
• Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs?

  2006cited by this paper
• NF-kappaB and Hsp70 are involved in the phospholipase Cgamma1 signaling pathway in colorectal cancer cells.

  2005cited by this paper
• Digitalis-Induced Signaling by Na+/K+-ATPase in Human Breast Cancer Cells

  2005cited by this paper
• NF-κB and Hsp70 are involved in the phospholipase Cγ1 signaling pathway in colorectal cancer cells

  2005cited by this paper
• Gastrin exerts pleiotropic effects on human melanoma cell biology.

  2005cited by this paper
• Identification of a novel cardenolide (2''-oxovoruscharin) from Calotropis procera and the hemisynthesis of novel derivatives displaying potent in vitro antitumor activities and high in vivo tolerance: structure-activity relationship analyses.

  2005cited by this paper
• Lysosomes as targets for cancer therapy.

  2005influential reference
• Pathways of apoptotic and non-apoptotic death in tumour cells

  2004cited by this paper
• Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells.

  2004cited by this paper
• Ouabain Assembles Signaling Cascades through the Caveolar Na+/K+-ATPase*

  2004cited by this paper
• Multiple cell death pathways as regulators of tumour initiation and progression

  2004influential reference
• Heat Shock Protein 70 Promotes Cancer Cell Viability by Safeguarding Lysosomal Integrity

  2004cited by this paper
• Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization

  2004influential reference
• Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice

  2004influential reference
• Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues.

  2004cited by this paper
• Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks

  2004cited by this paper
• Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin.

  2004cited by this paper
• Death receptors in chemotherapy and cancer

  2004cited by this paper
• Involvement of Cdk5/p25 in Digoxin-triggered Prostate Cancer Cell Apoptosis*

  2004cited by this paper
• Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 cells.

  2004cited by this paper
• Taxane-platinum combinations in advanced non-small cell lung cancer: a review.

  2004cited by this paper
• Silencing of TonEBP/NFAT5 transcriptional activator by RNA interference.

  2003cited by this paper
• Evidence That Phosphatidylinositol 3-Kinase- and Mitogen-activated Protein Kinase Kinase-4/c-Jun NH2-terminal Kinase-dependent Pathways Cooperate to Maintain Lung Cancer Cell Survival*

  2003cited by this paper
• Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells

  2003cited by this paper
• Induction of Heat Shock Protein 70 Inhibits NF-kappa-B in Squamous Cell Carcinoma

  2003cited by this paper
• Potent Killing of Paclitaxel- and Doxorubicin-resistant Breast Cancer Cells by Calphostin C Accompanied by Cytoplasmic Vacuolization

  2003cited by this paper
• Cell death induced by down-regulation of heat shock protein 70 in lung cancer cell lines is p53-independent and does not require DNA cleavage.

  2003influential reference
• Cardiac steroids induce changes in recycling of the plasma membrane in human NT2 cells.

  2003cited by this paper
• CAIR-1/BAG-3 Abrogates Heat Shock Protein-70 Chaperone Complex-mediated Protein Degradation

  2003cited by this paper
• Ineffectiveness of Histone Deacetylase Inhibitors to Induce Apoptosis Involves the Transcriptional Activation of NF-κB through the Akt Pathway*

  2003influential reference
• Na(+)/K(+)-ATPase as a signal transducer.

  2002cited by this paper
• Cardiotonic Steroids: Potential Endogenous Sodium Pump Ligands with Diverse Function11

  2002cited by this paper
• Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion.

  2002cited by this paper
• Novel Signal Transduction Pathway Utilized by Extracellular HSP70

  2002influential reference
• Regulation of TonEBP transcriptional activator in MDCK cells following changes in ambient tonicity.

  2002cited by this paper
• Selective cyclooxygenase-2 inhibitors and non-small cell lung cancer.

  2002cited by this paper
• An Alternative, Non-Apoptotic Form of Programmed Cell Death

  2001cited by this paper
• Cardenolides and cancer.

  2001cited by this paper
• Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells.

  2001cited by this paper
• Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells.

  2000cited by this paper
• p53 promotes selection for Fas-mediated apoptotic resistance.

  2000cited by this paper
• Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase.

  2000cited by this paper
• Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2.

  2000cited by this paper
• An alternative, nonapoptotic form of programmed cell death.

  2000cited by this paper
• Heat shock proteins as cellular lifeguards.

  1999cited by this paper
• Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis).

  1997cited by this paper
• Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells.

  1997cited by this paper
• P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo.

  1996cited by this paper
• Influence of gastrin on human astrocytic tumor cell proliferation.

  1996cited by this paper
• Anti-tumor promoting activities of natural products. II. Inhibitory effects of digitoxin on two-stage carcinogenesis of mouse skin tumors and mouse pulmonary tumors.

  1993cited by this paper
• Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells.

  1991cited by this paper
• Influence of pituitary grafts or prolactin administrations on the hormone sensitivity of ovarian hormone-independent mouse mammary MXT tumors.

  1989cited by this paper
• A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins.

  1989cited by this paper
• Paradoxical angina after nitroglycerin--another variant.

  1982cited by this paper
• Cardiac glycosides and breast cancer, revisited.

  1982cited by this paper
• Paradoxical angina after nitroglycerin--another variant.

  1982cited by this paper

• NFAT5 Regulates IL8 to Promote Cell Growth and Migration in Non‐Small Cell Lung Cancer

  2025cites this paper
• Elucidating the Complex Structural and Molecular Mechanisms Driving P-Glycoprotein-Mediated Transport of Cardiac Glycosides

  2025cites this paper
• Ouabain – a double-edged sword in tumor development and progression? a review of half a century

  2025cites this paper
• Cardiac glycosides with cytotoxic activity from the seeds of Thevetia peruviana.

  2024cites this paper
• Quantification of plant cardenolides by HPLC, measurement of Na+/K+-ATPase inhibition activity, and characterization of target enzymes.

  2023cites this paper
• Modern methods for identification and quantification of cardiac glycosides

  2023cites this paper
• Cardenolide Increase in Foxglove After 2,1,3-Benzothiadiazol Treatment Reveals a Potential Link Between Cardenolide and Phytosterol Biosynthesis.

  2022cites this paper
• Cardenolide Increase in Foxglove During Stresses Corresponds to Cholesterol and Phytosterol Biosynthesis

  2021cites this paper
• Cardiac Glycoside Ouabain Exerts Anticancer Activity via Downregulation of STAT3

  2021cites this paper
• Expression, Prognosis and Gene Regulation Network of NFAT Transcription Factors in Non-Small Cell Lung Cancer

  2021cites this paper
• Emergence of Cardiac Glycosides as Potential Drugs: Current and Future Scope for Cancer Therapeutics

  2021cites this paper
• Cardiac glycosides inhibit cancer through Na/K-ATPase-dependent cell death induction.

  2020cites this paper
• Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis

  2020cites this paper
• The feasibility and usability of DNA-dot bioconjugation to antibody for targeted in vitro cancer cell fluorescence imaging.

  2020cites this paper
• Anticancer and Antiviral Properties of Cardiac Glycosides: A Review to Explore the Mechanism of Actions

  2020cites this paper
• Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors

  2019cites this paper
• Peruvoside targets apoptosis and autophagy through MAPK Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways in human cancers.

  2019cites this paper
• UNBS 1450 from as a regulator of signaling pathways involved in proliferation and cell death

  2019cites this paper
• Therapeutic Potential of Cardiac Glycosides Against Cancer

  2018cites this paper
• Hsp70: A Cancer Target Inside and Outside the Cell.

  2018cites this paper
• Characterisation of palytoxin from an undescribed Palythoa (Anthozoa: Zoantharia: Sphenopidae) with significant in vitro cytotoxic effects on cancer cells at picomolar doses

  2018cites this paper
• Antimalarial drugs trigger lysosome-mediated cell death in chronic lymphocytic leukemia (CLL) cells.

  2018cites this paper
• Prognostic significance of nuclear factor of activated T-cells 5 expression in non-small cell lung cancer patients who underwent surgical resection.

  2018cites this paper
• R esearch Progress in Antitumor Effects of Cardiac Glycosides from Streptocaulon griffithii

  2018cites this paper
• Update on the effects of the sodium pump α1 subunit on human glioblastoma: from the laboratory to the clinic

  2018cites this paper
• NFAT5 promotes in vivo development of murine melanoma metastasis.

  2018cites this paper
• Long-circulating and fusogenic liposomes loaded with a glucoevatromonoside derivative induce potent antitumor response.

  2018cites this paper
• Effective Antimalarial Activities of α-Hydroxy Diynes Isolated from Ongokea gore

  2018cites this paper
• Synthesis of Cardiac Steroids and Their Role on Heart Failure and Cancer

  2018cites this paper
• Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells

  2017cites this paper
• Effects of digoxin on cell cycle, apoptosis and NF-κB pathway in Burkitt’s lymphoma cells and animal model

  2017cites this paper
• Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy

  2017cites this paper
• COMPARISON OF THE EFFICACY OF ARV MEDICATIONS ALONE AND IN COMBINATION WITH HERBAL MEDICATIONS IN THE TREATMENT OF HIV AMONG NIGERIAN HIV+ PATIENTS

  2017cites this paper
• Cardiac glycosides: From molecular targets to immunogenic cell death

  2017cites this paper
• Lysosomes as Oxidative Targets for Cancer Therapy

  2017cites this paper
• Autocrine MCP-1/CCR2 signaling stimulates proliferation and migration of renal carcinoma cells.

  2016cites this paper
• Identification of compounds with anti-proliferative activity from the wood of Ficus elastica Roxb. ex Hornem. aerial roots.

  2016cites this paper
• LC/MS Methods for Targeted Lipid Analyses

  2016cites this paper
• In vitro culture of Digitalis L. (Foxglove) and the production of cardenolides: An up-to-date review

  2016cites this paper
• Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

  2016cites this paper
• Health effects of desalinated water: Role of electrolyte disturbance in cancer development.

  2016cites this paper
• Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism

  2016cites this paper
• Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450

  2015cites this paper
• Src mediates extracellular signal‐regulated kinase 1/2 activation and autophagic cell death induced by cardiac glycosides in human non‐small cell lung cancer cell lines

  2015cites this paper
• Antagonistic role of natural compounds in mTOR-mediated metabolic reprogramming.

  2015cites this paper
• Influence of Sugar Amine Regiochemistry on Digitoxigenin Neoglycoside Anticancer Activity.

  2015cites this paper
• Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events

  2015cites this paper
• Cytotoxic cardenolides from the latex of Calotropis procera.

  2015cites this paper
• Seaweed Carotenoids for Cancer Therapeutics

  2015cites this paper
• NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression.

  2015cites this paper
• Synergistic Effect of Immunoliposomal Gemcitabine and Bevacizumab in Glioblastoma Stem Cell-Targeted Therapy.

  2015cites this paper
• Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

  2014cites this paper
• A study on the mechanism for neuron protection by heat shock protein after pre-acupuncture

  2014cites this paper
• Combination of AG 490 , a Jak 2 inhibitor , and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak 2 / STAT 3 pathway

  2014cites this paper
• Na+/K+ ATPase inhibitors in cancer.

  2014cites this paper
• NFAT5-mediated expression of S100A4 contributes to proliferation and migration of renal carcinoma cells

  2014cites this paper
• Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells.

  2014cites this paper
• Combination of AG490, a Jak2 inhibitor, and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway.

  2014cites this paper
• Targeting Susceptible Signaling Pathways in Chronic Lymphocytic Leukemia

  2014cites this paper
• 21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions

  2014cites this paper
• Contribution à l'étude phytochimique de Solidago virgaurea : application dans le domaine bucco-dentaire et étude de la variabilité phytochimique pour la création d'une filière

  2013cites this paper
• Assembling the puzzle of anti-cancer mechanisms triggered by cardiac glycosides.

  2013cites this paper
• Structure-activity relationship analysis of bufadienolide-induced in vitro growth inhibitory effects on mouse and human cancer cells.

  2013cites this paper
• Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials

  2013cites this paper
• Hellebrin and its aglycone form hellebrigenin display similar in vitro growth inhibitory effects in cancer cells and binding profiles to the alpha subunits of the Na+/K+-ATPase

  2013cites this paper
• Cardiotonic Steroids-Mediated Na+/K+-ATPase Targeting Could Circumvent Various Chemoresistance Pathways

  2013cites this paper
• New 5-Aryl-1H-imidazoles display in vitro antitumor activity against apoptosis-resistant cancer models, including melanomas, through mitochondrial targeting.

  2013cites this paper
• Cytotoxic cardenolides from the root bark of Calotropis gigantea.

  2013cites this paper
• Ouabain, a Cardiac Glycoside, Inhibits the Fanconi Anemia/BRCA Pathway Activated by DNA Interstrand Cross-Linking Agents

  2013cites this paper
• Anticancer steroids: linking natural and semi-synthetic compounds.

  2013cites this paper
• Synthesis and biological evaluation of analogs of the marine alkaloids granulatimide and isogranulatimide.

  2012cites this paper
• Ceramide, cerebroside and triterpenoid saponin from the bark of aerial roots of Ficus elastica (Moraceae).

  2012cites this paper
• “The Lower Threshold” phenomenon in tumor cells toward endogenous digitalis-like compounds: Responsible for tumorigenesis?

  2012cites this paper
• Secondary Metabolites from a Culture of the Fungus Neosartorya pseudofischeri and Their In Vitro Cytostatic Activity in Human Cancer Cells

  2012cites this paper
• Cardiotonic steroids-mediated targeting of the Na(+)/K(+)-ATPase to combat chemoresistant cancers.

  2012cites this paper
• Cardiac glycosides induce autophagy in human non-small cell lung cancer cells through regulation of dual signaling pathways.

  2012cites this paper
• Modulators of Na/K-ATPase: a patent review

  2012cites this paper
• Potential anticancer activity of young Carpinus betulus leaves.

  2012cites this paper
• New ursane-type triterpenes from the root bark of Calotropis procera

  2012cites this paper
• Nontargeted profiling of specialized metabolites of digitalis purpurea with a focus on cardiac glycosides

  2012cites this paper
• Immunohistochemical Analyses of α1 and α3 Na + /K + -ATPase Subunit Expression in Medulloblastomas

  2011cites this paper
• Pleiotropic effects of cardioactive glycosides.

  2011cites this paper
• Natural Product Communications. 6(6):803-806, 2011 Cytotoxic Cardenolide and Sterols from Calotropis gigantea

  2011cites this paper
• Imaging of intracellular acidic compartments with a sensitive rhodamine based fluorogenic pH sensor.

  2011cites this paper
• Immunohistochemical analyses of alpha1 and alpha3 Na+/K+-ATPase subunit expression in medulloblastomas.

  2011cites this paper
• In search of a cytostatic agent derived from the alkaloid lycorine: synthesis and growth inhibitory properties of lycorine derivatives.

  2011cites this paper
• Evaluation of the anticancer activities of two fungal polycyclic ethanones, alternethanoxins A and B, and two of their derivatives.

  2011cites this paper
• Cytotoxic Cardenolide and Sterols from Calotropis Gigantea

  2011cites this paper
• N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b): a novel anticancer glycyrrhetinic acid derivative that targets the proteasome and displays anti-kinase activity.

  2011cites this paper
• In vitro growth inhibitory effects of cytochalasins and derivatives in cancer cells.

  2011cites this paper
• Lysosomal membrane permeabilization is involved in curcumin-induced apoptosis of A549 lung carcinoma cells

  2011cites this paper
• Evaluation of the antiproliferative activity of diterpene isonitriles from the sponge Pseudoaxinella flava in apoptosis-sensitive and apoptosis-resistant cancer cell lines.

  2011cites this paper
• UNBS1450, a steroid cardiac glycoside inducing apoptotic cell death in human leukemia cells.

  2011cites this paper
• PREDICTIONS FOR HEAT SHOCK PROTEIN 70 RELATED GENE NETWORK AND METABOLITE CHANGES IN CALOTROPIS AND/OR FRUCTOSE FED RATS Research Article

  2011cites this paper
• Hsp70: anti-apoptotic and tumorigenic protein.

  2011cites this paper
• Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents.

  2011cites this paper
• JAK2/STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer.

  2011cites this paper
• Caractérisation des mécanismes de résistance des cellules gliales tumorales à la chimiothérapie et identification de nouvelles pistes chimiothérapeutiques potentielles

  2011cites this paper
• In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii.

  2011cites this paper
• Effets anticancéreux de UNBS1450 : cas de hémopathies malignes

  2010cites this paper