Cardiotonic steroids on the road to anti-cancer therapy

Mijatovic, Tatjana; Quaquebeke, Eric Van; Delest, Bruno; Debeir, Olivier; Darro, Francis; Kiss, Róbert

doi:10.1016/j.bbcan.2007.06.002

Cited by 208 publications

(313 citation statements)

References 172 publications

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“…In contrast, in other species, including humans, the affinity of α1 isoforms to cardiac glycosides is higher, causing a greater sensitivity to ouabain (31)(32)(33). Additionally, the rodent α1 isoform is almost 1,000 times less sensitive to cardiac glycosides than that in the human due to a double mutation in the first extracellular loop (18). After the assessment of adenocarcinomas and squamous cell carcinoma tissues from 59 patients with lung cancer, Mijatovic et al suggested that the α1 isoform of Na,K-ATPase may be a useful target for cardiac glycosides in the treatment of non-small cell lung cancer cells (34).…”

Section: Discussionmentioning

confidence: 82%

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Yang

Menter

Cartwright

et al. 2009

Molecular Cancer Therapeutics

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Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase α3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of α3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of α3 to α1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the α3 expression relative to α1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of α3 was decreased by knocking down the expression of α3 isoform with α3 siRNA or increasing expression of the α1 isoform through transient transfection of α1 cDNA to the cells. Our data suggest that the relative lack of α3 (relative to α1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of α3 with the limited expression of α1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin.

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Section: Discussionmentioning

confidence: 82%

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Yang

Menter

Cartwright

et al. 2009

Molecular Cancer Therapeutics

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“…Although some of the differentially expressed proteins in ADPKD mice, such as Na ϩ /K ϩ -ATPase, have been demonstrated to play a critical role in the development of the cystic phenotype, they have not been tested as potential targets for treatment of ADPKD or renal disease. Because Na ϩ /K ϩ -ATPase is a clinically relevant drug target for cardiovascular disease (52) as well as cancer (53), whether it can potentially be targeted for ADPKD remains open to further investigation. Given the possibilities offered by our new technique for more efficient identification and quantification of large numbers of transporters/receptors, we expect to systematically decipher the mechanism of cystogenesis and identify additional drug target candidates in the near future.…”

Section: Systemic Manifestation Of the Altered Membrane Proteome Provmentioning

confidence: 99%

A Multiplexed Quantitative Strategy for Membrane Proteomics

Han

Chien

Chen³

et al. 2008

Molecular & Cellular Proteomics

130

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Toward multiplexed, comprehensive, and robust quantitation of the membrane proteome, we report a strategy combining gel-assisted digestion, iTRAQ (isobaric tags for relative and absolute quantitation) labeling, and LC-MS/MS. Quantitation of four independently purified membrane fractions from HeLa cells gave high accuracy (<8% error) and precision (<12% relative S.D.), demonstrating a high degree of consistency and reproducibility of this quantitation platform. Under stringent identification criteria (false discovery rate ‫؍‬ 0%), the strategy efficiently quantified membrane proteins; as many as 520 proteins (91%) were membrane proteins, each quantified based on an average of 14.1 peptides per integral membrane protein. In addition to significant improvements in signal intensity for most quantified proteins, most remarkably, topological analysis revealed that the biggest improvement was achieved in detection of transmembrane peptides from integral membrane proteins with up to 19 transmembrane helices. To the best of our knowledge, this level of coverage exceeds that achieved previously using MS and provides superior quantitation accuracy compared with other methods. We applied this approach to the first proteomics delineation of phenotypic expression in a mouse model of autosomal dominant polycystic kidney disease (ADPKD). By characterizing kidney cell plasma membrane from wild-type versus PKD1 knock-out mice, 791 proteins were quantified, and 67 and 37 proteins showed >2-fold up-regulation and down-regulation, respectively. Some of these differentially expressed membrane proteins are involved in the mechanisms underlying major abnormalities in ADPKD, including epithelial cell proliferation and apoptosis, cell-cell and cell-matrix interactions, ion and fluid secretion, and membrane protein polarity. Among these proteins, targeting therapeutics to certain transporters/receptors, such as epidermal growth factor receptor, has proven effective in preclinical studies of ADPKD; others are known drug targets in various diseases. Our method demonstrates how comparative membrane proteomics can provide insight into the molecular mechanisms underlying ADPKD and the identification of potential drug targets, which may lead to new therapeutic opportunities to prevent or retard the disease.

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“…In the present study we have investigated the ability of ISP in inducing apoptosis in vitro in two types of apoptosis-resistant cancers, i.e., glioblastoma (GBM) (10)(11)(12) and non-small cell lung cancer (NSCLC) (13,14). 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.…”

Section: Introductionmentioning

confidence: 99%

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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Cardiotonic steroids on the road to anti-cancer therapy

Cited by 208 publications

References 172 publications

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

A Multiplexed Quantitative Strategy for Membrane Proteomics

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

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