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

Platz, Elizabeth A.; Yegnasubramanian, Srinivasan; Liu, Jun O.; Chong, Curtis R.; Shim, Joong Sup; Kenfield, Stacey A.; Stampfer, Meir J.; Willett, Walter C.; Giovannucci, Edward; Nelson, William G.

doi:10.1158/2159-8274.cd-10-0020

Cited by 158 publications

(165 citation statements)

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“…In drug screening, digoxin was found to be among the most potent of commonly used drugs in inhibiting growth of prostate cancer cell lines (25). In the same study, the investigators examined risk in men using digoxin, finding a lower prostate cancer incidence (0.76; 95% CI, 0.61-0.95), compared with nonusers of digoxin (25). Further studies are needed to confirm this result, but the result is consistent with digoxin exerting an estrogenic effect.…”

Section: Digitalis and Cancer Riskmentioning

confidence: 99%

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Biggar

2012

Clinical Cancer Research

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Digoxin, a phyto-estrogen, binds with estrogen receptors (ER) and can cause gynecomastia. Among women currently using digoxin, breast and uterus cancer incidences are significantly increased (approximate risk ratios, 1.3-1.5). Both cancers are often estrogen sensitive. In contrast, ovary and cervix cancers are relatively estrogen insensitive, and incidence is unaffected by digoxin exposure. When digoxin use stops, incidence rapidly reverts to that in nonusers. These patterns parallel those of estrogen, suggesting that digoxin works via ER-stimulated proliferation of ductal and/or acinar cells, accelerating the growth of nascent cancers. Also consistent with an estrogenic effect, men using digoxin have a small but significant reduction in prostate cancer (risk ratio, 0.76). Other estrogen-like drugs, particularly spironolactone, should be investigated for similar effects. The effect of digoxin use in women being treated for breast cancer or in survivors is unknown. Women with estrogen-sensitive cancers on adjuvant therapy may take tamoxifen, which blocks ERs. However, postmenopausal patients may use aromatase inhibitors, which block estrogen production while leaving ERs susceptible to digoxin. If adverse effects are found, tamoxifen may be preferred over aromatase inhibitors in patients receiving estrogen-mimicking drugs. Alternatively, other cardiotropic drugs might be considered in women with or at high risk of developing estrogen-sensitive cancers.

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Section: Digitalis and Cancer Riskmentioning

confidence: 99%

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Biggar

2012

Clinical Cancer Research

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“…Importantly and most excitingly, bufalin sensitizes breast and lung cancer cells to the inhibitory effects of other chemotherapeutics and inhibits primary tumor growth in vivo. Other groups also reported that bufalin and other cardiac glycosides can inhibit transcription factors and induce synergistic immune responses (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Unfortunately, cardiac glycosides are well known for their cardiotoxicity.…”

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confidence: 99%

Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3

Song

Chen

Zhao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for highthroughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein.Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC 50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.steroid receptor coactivator | small-molecule inhibitor | breast cancer | drug development | protein-protein interactions P rotein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development (1). Biologics-based therapeutics, such as antibodies, exemplify success in PPI regulation (2). However, antibodies usually can only be applied to protein targets on cell surfaces because of their impermeability to plasma membranes (2). Although small-molecule drugs can readily cross membranes, applying small-molecule inhibitors (SMIs) to disrupt PPIs is a challenging task because ∼750-1,500 Å 2 of protein surface area is involved at the interface of PPIs (3), which is too large for SMIs to cover. In addition, these interacting protein surfaces do not have pocket-like small-molecule binding sites (2). Therefore, these PPI sites are deemed as "undruggable" targets for SMIs. The Holy Grail of drug development is to render small molecules the power of biologics to regulate PPIs.The current strategies for designing small-molecule PPI inhibitors primarily rely on the structural information of the protein targets (4). Clackson and Wells discovered that only a small set of residues at the PPI interface are critical for their interactions, known as "hot spots" (5). Therefore, current drug design for PPIs is mainly focused on small hot spots that can be covered by a dru...

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“…As with any observational study, biases could partially account for these findings. Digoxin users were more likely to be white, less likely to have a family history of prostate cancer, and more likely to use cholesterollowering drugs and aspirin regularly, all factors that could contribute to the findings reported by Platz and colleagues (4). In addition, digoxin users tended to be older (and therefore may have surpassed the peak age of receiving a diagnosis of prostate cancer) or, because of their cardiac problems, may not have lived long enough to develop prostate cancer, circumstances also possibly contributing to a reduced risk of prostate cancer in digoxin users.…”

Section: In the Spotlightmentioning

confidence: 82%

Epidemiology—Found in Translation

Spitz

Caporaso²,

Freedman³

2011

Cancer Discovery

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We highlight the value of carefully designed observational epidemiologic analyses in translating basic science discoveries to clinical application and in providing the impetus for exploring underlying mechanisms for observed associations. Coupling epidemiologic data with an in vitro screen of commonly used therapeutic agents may identify novel applications for further clinical testing. Cancer Discovery; 1(1); 21–2. ©2011 AACR. Commentary on Platz et al., p. 68

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

Cited by 158 publications

References 23 publications

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3

Epidemiology—Found in Translation

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