Effects of ouabain on NIH/3T3 cells transformed with retrovirai oncogenes and on human tumor cell lines

Tagliaferri, Pierosandro; Yanagihara, Kazuyoshi; Ciardiello, F.; Talbot, Neil C.; Flatow, Ursula; Benade, Leonard E.; Bassin, Robert H.

doi:10.1002/ijc.2910400514

Cited by 8 publications

(2 citation statements)

References 10 publications

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“…Gynecomastia is reported to be a side effect of digoxin possibly caused by shared structure with steroids including estrogen (15); estrogen has long been used to treat advanced prostate cancer. Interestingly, ouabain could selectively inhibit proliferation of oncogene-transformed cells compared to untransformed cells (16, 17), suggesting that a synthetic lethality paradigm may allow sparing of normal cells despite cytotoxicity of oncogene-transformed malignant cells. Whether the same differential effect would be observed for digoxin and prostate cancer cells with their array of oncogenic alterations remains to be assessed, but these findings suggest the intriguing possibility that a synthetic lethality paradigm (18) could be exploited in the development of digoxin and other cardiac glycosides as a prostate cancer drug.…”

Section: Discussionmentioning

confidence: 99%

A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment

Platz

Yegnasubramanian²,

Liu³

et al. 2011

Cancer Discovery

158

154

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Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically-used drugs might have utility for treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large, prospective cohort study. In stage 1, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate given its potency in inhibiting proliferation in vitro (mean IC50=163 nM) and common use. In stage 2, we evaluated the association between the leading candidate drug from stage 1 and prostate cancer risk in 47,884 men followed 1986–2006. Regular digoxin users (versus nonusers: RR=0.76, 95% CI 0.61–0.95), especially users for ≥10 years (RR=0.54, 95% CI 0.37–0.79, P-trend<0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro and its use was associated with a 25% lower prostate cancer risk.

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Section: Discussionmentioning

confidence: 99%

A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment

Platz

Yegnasubramanian²,

Liu³

et al. 2011

Cancer Discovery

158

154

View full text Add to dashboard Cite

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“…In light of the reports suggesting different sensitivities of tumor and nontumor cells to CGs (5,8,27,35,37), it was of special interest to compare tumor-derived cell lines with nontransformed cells as well as the isoform expression pattern because some cancer cells express ␣3 rather than ␣1 (33, 38). Table 2 lists the 12 cell lines tested and their origin (transformed vs. nontransformed).…”

Section: C130 Isoforms Cardiac Glycoside Selectivity and Cell Deathmentioning

confidence: 99%

Cardiac glycosides induced toxicity in human cells expressing α1-, α2-, or α3-isoforms of Na-K-ATPase

Lev

Karlish

Garty

2015

American Journal of Physiology-Cell Physiology

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Cherniavsky Lev M, Karlish SJ, Garty H. Cardiac glycosides induced toxicity in human cells expressing ␣1-, ␣2-, or ␣3-isoforms of Na-K-ATPase. Am J Physiol Cell Physiol 309: C126 -C135, 2015. First published May 20, 2015 doi:10.1152/ajpcell.00089.2015.-The Na ϩ -K ϩ -ATPase is specifically inhibited by cardiac glycosides, some of which may also function as endogenous mammalian hormones. Previous studies using Xenopus oocytes, yeast cells, or purified isoforms demonstrated that affinities of various cardiac glycosides for three isoforms of the Na ϩ -K ϩ -ATPase (␣1-␣3␤1) may differ, a finding with potential clinical implication. The present study investigates isoform selectivity and effects of cardiac glycosides on cultured mammalian cells under more physiological conditions. H1299 cells (non-small cell lung carcinoma) were engineered to express only one ␣-isoform (␣1, ␣2, or ␣3) by combining stable transfection of isoforms and silencing endogenous ␣1. [21153][21154][21155][21156][21157][21158][21159][21160][21161][21162] 2014). Relative ␣2:␣1 selectivity of digoxin vs. ouabain was also manifested by enhanced internalization of ␣2 in response to digoxin. Cellular proliferation assays of H1299 cells confirmed the patterns of ␣2:␣1 selectivity for ouabain, digoxin, and a synthetic derivative and reveal a crucial role of surface pump density on sensitivity to cardiac glycosides. Because cardiac glycosides are being considered as drugs for treatment of cancer, effects of ouabain on proliferation of 12 cancer and noncancer cell lines, with variable plasma membrane expression of ␣1, have been tested. These demonstrated that sensitivity to ouabain indeed depends linearly on the plasma membrane surface density of Na ϩ -K ϩ -ATPase irrespective of status, malignant or nonmalignant. cardiac glycosides; cell death; isoforms; Na-K-ATPase THE NA ϩ -K ϩ -ATPASE (the Na ϩ pump) is a ubiquitously expressed P-type ATPase that actively transports 3Na ϩ ions out of cells in exchange for 2K ϩ ions per one molecule of ATP hydrolyzed (17). The pump consists of a catalytic ␣-subunit, ␤-subunit that modulates activity and stabilizes the protein, and an auxiliary FXYD polypeptide. Four ␣-isoforms (␣1-␣4), three ␤-isoforms (␤1-␤3), and seven FXYD isoforms exist in mammalian organisms, resulting in considerable tissue-specific variability in pump structure and kinetics (21).As can be expected from plasma membrane protein with such a vital function, the Na ϩ -K ϩ -ATPase is regulated by a number of independent mechanisms (25). One such mode of regulation involves inhibition by a family of inhibitors termed cardiac glycosides (CGs). Most CGs are derived from plants.However, several so-called endogenous CGs, including ouabain, marinobufagenin, and digoxin, have been identified in mammalian tissues and are apparently synthesized by the adrenal gland (1). CGs such as digoxin are also clinically relevant specific inhibitors of the Na ϩ -K ϩ -ATPase, used classically to treat heart failure (9).Relatively limited information exists regarding th...

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Establishment and characterization of a human gastric scirrhous carcinoma cell line in serum‐free chemically defined medium

Yanagihara

Kamada

Tsumuraya

et al. 1993

Intl Journal of Cancer

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We have established a human gastric scirrhous carcinoma cell line (designated as HSC-43) in a serum-free chemically defined medium (CDM) without any polypeptide growth factor, from a primary tumor of a 56-year-old male patient. HSC-43 cells grew in vitro in adherence with a population doubling time of 55 hr, and had the cytological properties of mucinous epithelial tumor cells. Cytogenetic analysis of the cells revealed pseudotetraploidy, with structural abnormalities of deletion at chromosome Iq25 and with 3 marker chromosomes. Some cells had retained features of signet-ring cells and caused fibroblastic proliferation when transplanted into athymic nude mice. The possible involvement of transforming growth factor-alpha (TGF-alpha), and its receptor, the epidermal-growth-factor receptor (EGFR), on the growth of HSC-43 cells was studied. Synthesis and secretion of TGF-alpha by HSC-43 cells were confirmed by biological assay and enzyme-linked immunosorbent assay. Radioreceptor analysis showed the presence of receptors for EGF in HSC-43 cells. Proliferation of HSC-43 cells was inhibited by antibodies against TGF-alpha and/or the EGFR. However, neither TGF-alpha nor epidermal growth factor (EGF) was effective in stimulating the cell growth of HSC-43 cells, irrespective of the cell density when supplemented exogenously. Our data suggest that TGF-alpha and EGFR play a role in the autocrine growth of HSC-43 cells. This may be another example of growth regulation of gastric carcinoma.

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Effects of ouabain on NIH/3T3 cells transformed with retrovirai oncogenes and on human tumor cell lines

Cited by 8 publications

References 10 publications

A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment

A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment

Cardiac glycosides induced toxicity in human cells expressing α1-, α2-, or α3-isoforms of Na-K-ATPase

Establishment and characterization of a human gastric scirrhous carcinoma cell line in serum‐free chemically defined medium

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