Targeting the Α 1 Subunit of the Sodium Pump to Combat Glioblastoma Cells

Lefranc, Florence; Mijatovic, Tatjana; Kondo, Yasuko; Sauvage, Sébastien; Roland, Isabelle; Debeir, Olivier; Krstić, Danijela; Vasic, M Vesna; Gailly, Philippe; Kondo, Seiji; Blanco, Gustavo; Kiss, Róbert

doi:10.1227/01.neu.0000311080.43024.0e

Cited by 154 publications

(198 citation statements)

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“…The overall growth level of human U373, A549 and PC-3 cancer cells was determined by means of the MTT colorimetric assay as detailed elsewhere (15,17,18). The cancer cells were cultured for 3 days in the presence (or absence as a control) of ISP concentrations ranging from 1 nM to 10 μM.…”

Section: Isp In Vitro Growth Inhibitory Activitymentioning

confidence: 99%

“…[ATP] i was measured using a bioluminescence assay (Invitrogen, Merelbeke, Belgium) in U373 GBM and A549 NSCLC cells cultured in the presence (or absence as a control) of ISP at its IC 50 concentrations (~1 μM), as detailed elsewhere (17,23). Three replicate determinations per time point were performed for each cell line.…”

Section: Cellular Atp ([Atp] I ) Measurementsmentioning

confidence: 99%

“…ISP induces cytotoxic effects in human U373 GBM cells. The human U373 GBM cells resist many types of pro-apoptotic stimuli even when the pro-apoptotic compounds are analyzed at concentrations up to 10-fold the compound-related IC 50 concentrations (17,18,23). Fig.…”

Section: Determination Of Isp Ic 50 In Vitro Growth Inhibitory Concenmentioning

confidence: 99%

“…We used as a positive control the human PC-3 prostate cancer cell line in which plantderived compounds, such as narciclasine (15) or sodium pump inhibitors (16) are able to induce apoptosis in vitro. Narciclasine and sodium pump inhibitors are not able to induce apoptosis in vitro in the U373 GBM (17,18) and A549 NSCLC (19) models: these two models therefore display a certain level of resistance to apoptosis. (15,17,18).…”

Section: Introductionmentioning

confidence: 99%

“…Narciclasine and sodium pump inhibitors are not able to induce apoptosis in vitro in the U373 GBM (17,18) and A549 NSCLC (19) models: these two models therefore display a certain level of resistance to apoptosis. (15,17,18). ISP was obtained as described elsewhere (9); its chemical structure is illustrated in Fig.…”

Section: Introductionmentioning

confidence: 99%

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Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

Baldé

Mégalizzi²,

Cao³

et al. 2010

Int J Oncol

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Abstract. Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, an East African small tree. We have reported previously pro-apoptotic effects induced in vitro by ISP in the human HCT-116 colon cancer cell line, a model that displays relative sensitivity to apoptosis. In the present study, we observed that the in vitro growth inhibitory activities of ISP are similar in cancer cells that display sensitivity versus resistance to apoptosis. We made use of the U373 glioblastoma and the A549 non-small cell lung cancer (NSCLC) cell lines as models relatively resistant to apoptosis, and the human PC-3 prostate cancer cell line as a model relatively sensitive to apoptosis. While ISP induced transient decreases in [ATP] i and apoptosis in human U373 GBM cells, it did not provoke such features in A549 NSCLC cells. It thus seems that ISPinduced anti-cancer activity can lead to pro-apoptotic effects as a consequence, while apoptosis seems not to be the main cause by which ISP induces cancer cell death. ISP is a compound that merits further investigations in order to: i) identify the mechanism(s) of action by which it kills cancer cells, and ii) hemisynthesize novel ISP derivatives aiming to overcome, at least partly, the resistance of metastatic cancers to apoptosis. IntroductionDespite frequent responses to chemotherapy, curative treatment remains elusive for the majority of patients with metastatic solid tumors (1). Indeed, in the common advanced cancers, over 40 years of cytotoxic drug development has brought no significant change in cure rates (1). Savage and colleagues (1) report that one interpretation is that the intrinsic properties of the malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. These authors thus suggest that the curability of these malignancies results from an intrinsic 'locked-in' state of sensitivity to proapoptotic stresses in these cells (1). In fact, >90% of cancer patients die from their metastases (2). Drug resistance, either acquired or intrinsic, often prevents tumor cells from undergoing sufficient levels of apoptosis, resulting in cancer cell survival and treatment failure (1,2). The metastatic process is inherent to a significant level of resistance to apoptosis. Indeed, as a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighboring cells (3). This cell death process has been termed 'anoikis' (3). Tumor cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems (3). Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to anoïkis (3).Plants have played a dominant role in the development of sophisticate...

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Section: Isp In Vitro Growth Inhibitory Activitymentioning

confidence: 99%

Section: Cellular Atp ([Atp] I ) Measurementsmentioning

confidence: 99%

Section: Determination Of Isp Ic 50 In Vitro Growth Inhibitory Concenmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

Baldé

Mégalizzi²,

Cao³

et al. 2010

Int J Oncol

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Engineered Exosomes with Ouabain for H3K27M‐Mutated DIPG Therapy

Shan,

Chen,

Qing

et al. 2024

Adv Funct Materials

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Diffuse intrinsic pontine glioma (DIPG) is a highly lethal tumor that occurs in the brain stem. At present, there is no effective drug for DIPG. In this work, Na/K‐ATPase inhibitor‐ouabain (OB) is found to efficiently kill H3K27M‐mutated DIPG at low doses, inhibit tumor cell proliferation, reduce tumor stemness for the first time, demonstrating its potential as a chemotherapy drug for DIPG. In order to increase the blood–brain barrier (BBB) permeability and tumor accumulation of OB, acidic‐responsive engineered exosomes loaded with OB (OB@EXO‐LCCP) are constructed, which increase the accumulation of OB within the tumor microenvironment of DIPG and efficiently deliver OB to DIPG cells to achieve targeted killing effect. In in vitro experiments, OB@EXO‐LCCP is able to release OB in an acid‐responsive manner and effectively kill DIPG tumor cells. In in vivo experiments, OB@EXO‐LCCP significantly inhibits DIPG growth and prolongs the overall survival of DIPG‐bearing mice. Overall, OB@EXO‐LCCP can promote the BBB permeability and tumor‐targeting ability of OB, thereby enhancing its DIPG‐killing ability and reducing its toxicity. This study provides technical and theoretical information for the precision therapy of DIPG.

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Marinobufagenin inhibits glioma growth through sodium pump α1 subunit and ERK signaling‐mediated mitochondrial apoptotic pathway

et al. 2018

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Malignant glioma is one of the most challenging central nervous system diseases to treat and has high rates of recurrence and mortality. Current therapies often fail to control tumor progression or improve patient survival. Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in sodium pump inhibition. Currently, various studies have indicated the potential of MBG in cancer treatments; however, the precise mechanisms are poorly understood. The functions of MBG were examined using colony formation, migration, cell cycle, and apoptosis assays in glioma cells. A mitochondrial membrane potential assay was performed to determine the mitochondrial transmembrane potential change, and cytochrome c release from mitochondria was assayed by fluorescence microscopy. An immunofluorescence assay was performed, and the nuclear translocation of NF‐κB in glioma cells was confirmed by confocal microscopy. Western blotting and RT‐qPCR were used to detect the protein and gene expression levels, respectively. In addition, transfection experiment of ATP1A1‐siRNA was further carried out to confirm the role of sodium pump α1 subunit in the anticancer effect of MBG in human glioma. The apoptosis‐promoting and anti‐inflammatory effects of MBG were further investigated, and the sodium pump α1 subunit and the ERK signaling pathway were found to be involved in the anticancer effect of MBG. The in vivo anticancer efficacy of MBG was also tested in xenografts in nude mice. Thus, therapies targeting the ERK signaling‐mediated mitochondrial apoptotic pathways regulated by MBG might represent potential treatments for human glioma, and this study could accelerate the finding of newer therapeutic approaches for malignant glioma treatment.

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Targeting the Α 1 Subunit of the Sodium Pump to Combat Glioblastoma Cells

Abstract: Inhibition of the Na+/K+ -ATPase alpha1 subunit in human GBM cells impairs both cell migration and cell proliferation.

Cited by 154 publications

References 43 publications

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

Engineered Exosomes with Ouabain for H3K27M‐Mutated DIPG Therapy

Marinobufagenin inhibits glioma growth through sodium pump α1 subunit and ERK signaling‐mediated mitochondrial apoptotic pathway

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