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Nature Jul 2016Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved...
Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resolution apo structure gives a more complete and accurate picture of the molecule, and allows conformational changes introduced by antibody and receptor binding to be deciphered. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equivalent tunnels from the other monomers of the trimer at the three-fold axis. Protein–drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14 °C decrease in the protein melting temperature after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Binding Sites; Cell Line; Conserved Sequence; Ebolavirus; Endosomes; Humans; Hydrophobic and Hydrophilic Interactions; Ibuprofen; Ligands; Marburgvirus; Membrane Fusion; Models, Molecular; Protein Binding; Protein Stability; Protein Structure, Quaternary; Protein Subunits; Temperature; Toremifene; Viral Envelope Proteins; Virus Attachment
PubMed: 27362232
DOI: 10.1038/nature18615 -
Prostate Cancer and Prostatic Diseases Mar 2010Bone metastases are a substantial burden to men with advanced prostate cancer as they often cause pain and can cause fractures and spinal cord compression. Osteoblasts... (Review)
Review
Bone metastases are a substantial burden to men with advanced prostate cancer as they often cause pain and can cause fractures and spinal cord compression. Osteoblasts and osteoclasts are both pathologically activated in the setting of prostate cancer bone metastases. As osteoclast activation is associated with disease progression, skeletal complications and death, osteoclast-targeted therapies are a rational approach to disease management. Zoledronic acid is standard of care for castration-resistant prostate cancer with bone metastases as it reduces the risk for skeletal-related events. Additional trials are needed to better define the ideal dose, frequency and duration of zoledronic acid therapy. No bisphosphonate has yet been shown to prevent bone metastases or to benefit men with androgen-sensitive disease. Denosumab is an experimental osteoclast-targeted monoclonal antibody against receptor activator of nuclear factor-kappaB ligand. Two ongoing phase III trials are expected to define its efficacy in preventing bone metastases and disease-related skeletal events in men with prostate cancer. Androgen-deprivation therapy (ADT) for prostate cancer is associated with osteoporosis and fragility fractures. Several bisphosphonates have been shown to improve bone mineral density in men receiving ADT. Two recent phase III trials have shown that denosumab and toremifene reduce the incidence of fragility fractures in these men. The World Health Organization has developed a fracture risk assessment model (FRAX) for the general population to guide the selection of patients who may benefit from pharmacotherapy. In the absence of a prostate cancer-specific algorithm, we advocate the use of FRAX for men receiving ADT.
Topics: Androgen Antagonists; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density; Bone Neoplasms; Clinical Trials as Topic; Denosumab; Diphosphonates; Fractures, Bone; Humans; Imidazoles; Male; Osteoclasts; Prostatic Neoplasms; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Zoledronic Acid
PubMed: 19901958
DOI: 10.1038/pcan.2009.50 -
MBio Dec 2018The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent... (Review)
Review
The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive. From these efforts, the triphenylethylene class of selective estrogen receptor modulators related to tamoxifen has shown activity against a wide range of medically important human pathogens, including bacteria, fungi, parasites, and viruses. Because it has activity against many pathogens affecting people in resource-limited areas of the world, TAM and related drugs may be particularly useful. Here, we review the , , and mechanistic studies of the anti-infective activity of tamoxifen, toremifene, clomiphene, and their analogs. We also discuss the pharmacologic properties of this privileged scaffold and its potential utility in treating infectious diseases.
Topics: Animals; Bacteria; Communicable Diseases; Drug Repositioning; Estrogen Receptor Antagonists; Female; Humans; Mice; Parasites; Stilbenes; Tamoxifen; Toremifene; Viruses
PubMed: 30563895
DOI: 10.1128/mBio.02272-18 -
Clinical Cancer Research : An Official... Oct 2006The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men. Consistent with this... (Review)
Review
The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men. Consistent with this observation, GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk. Large claims-based analyses and other retrospective studies provide compelling evidence that GnRH agonists increase risk of clinical fractures. Estrogens play a central role in homeostasis of the normal male skeleton, and estrogen deficiency rather than testosterone deficiency seems to be primarily responsible for the adverse skeletal effects of GnRH agonists. In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist-treated men. Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment.
Topics: Antineoplastic Agents; Bone Density Conservation Agents; Humans; Male; Osteoporosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 17062721
DOI: 10.1158/1078-0432.CCR-06-0846 -
Clinical Breast Cancer Feb 2014Endocrine therapy is a cornerstone of medical treatment for estrogen receptor-positive breast cancer. The discovery of selective estrogen receptor modulators (SERMs) >... (Review)
Review
Endocrine therapy is a cornerstone of medical treatment for estrogen receptor-positive breast cancer. The discovery of selective estrogen receptor modulators (SERMs) > 40 years ago represented a revolutionary advance in the treatment of breast cancer. As a therapeutic class, SERMs have either estrogenic or antiestrogenic activity, depending on the target tissue and the hormonal environment. In breast tissue, SERMs are antiestrogenic, making them a major treatment option for women with hormone-sensitive breast cancer. Toremifene citrate was developed > 20 years ago with the goal of achieving efficacy similar to that of tamoxifen and with an improved safety profile. Although studies to date have not confirmed a clear safety advantage or disadvantage for toremifene, clinical data support the efficacy and safety of toremifene for the treatment of breast cancer in postmenopausal patients. Toremifene also has a pharmacokinetic profile and metabolic pathway different from that of tamoxifen, which may provide a therapeutic advantage in certain patients. In addition, because of the selective estrogenic effects of SERMs in bone and on lipid levels along with a different side effect profile compared with the aromatase inhibitors (AIs), toremifene is a viable option to the AIs for some patients. Despite a number of clinical trials and over 500,000 patient years of use, many oncologists have limited familiarity with toremifene data. This article will examine the rationale for the use of toremifene in the treatment of women with breast cancer and review data from 20 years of clinical experience with this agent.
Topics: Adult; Aged; Aged, 80 and over; Aromatase Inhibitors; Bone Density; Breast Neoplasms; Cytochrome P-450 CYP2D6; Drug Resistance, Neoplasm; Female; Humans; Lipids; Middle Aged; Postmenopause; Selective Estrogen Receptor Modulators; Toremifene
PubMed: 24439786
DOI: 10.1016/j.clbc.2013.10.014 -
Current Oncology (Toronto, Ont.) Aug 2013Given the use of tamoxifen as standard treatment for hormone receptor-positive breast cancer, the use of toremifene as an adjuvant endocrine therapy has not been widely...
BACKGROUND
Given the use of tamoxifen as standard treatment for hormone receptor-positive breast cancer, the use of toremifene as an adjuvant endocrine therapy has not been widely examined. The present retrospective study compared the efficacy and safety of toremifene and tamoxifen in the treatment of operable hormone receptor-positive breast cancer in premenopausal women.
METHODS
Premenopausal patients with hormone receptor- positive operable breast cancer were eligible. Enrolled patients (n = 1847) received either 60 mg toremifene (n = 396) or 20 mg tamoxifen (n = 1451) daily for a minimum of 5 years after surgery. Disease-free survival (dfs) was the primary endpoint. Overall survival (os) and time to distant recurrence were secondary endpoints.
RESULTS
Treatment with toremifene and tamoxifen resulted in no between-group differences in dfs (p = 0.659) or os (p = 0.364). Mean dfs was 10.3 years for both groups. Mean os was 11.2 years for the toremifene group and 11.1 years for tamoxifen group. The 5-year dfs rate was 87.0% in the toremifene group and 85.0% in the tamoxifen group. The 5-year survival rate was 94.3% in the toremifene group and 93.5% in the tamoxifen group. Adverse events rates were similar in the two groups, with the exception of irregular menses, which occurred at a higher rate in the tamoxifen group than in the toremifene group (10.0% vs. 6.3%, p = 0.025).
CONCLUSIONS
In this retrospective study, the efficacy and safety profiles of toremifene and tamoxifen for the treatment of operable hormone receptor-positive breast cancer in premenopausal women were similar.
PubMed: 23904760
DOI: 10.3747/co.20.1231 -
Journal of Clinical Oncology : Official... Sep 2011Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly... (Review)
Review
Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Bone Neoplasms; Denosumab; Diphosphonates; Humans; Male; Prostatic Neoplasms; Proto-Oncogene Mas; RANK Ligand; Radiopharmaceuticals
PubMed: 21860001
DOI: 10.1200/JCO.2010.34.4994 -
The Cochrane Database of Systematic... Jul 2012Toremifene (TOR) and tamoxifen (TAM) can both be used as treatments for advanced breast cancer. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Toremifene (TOR) and tamoxifen (TAM) can both be used as treatments for advanced breast cancer.
OBJECTIVES
To compare the efficacy and safety of TOR with TAM in patients with advanced breast cancer.
SEARCH METHODS
The Cochrane Breast Cancer Group's Specialised Register was searched (1 July 2011) using the codes for "toremifene", "fareston", "tamoxifen, "nolvadex, and "breast cancer". We also searched MEDLINE (via PubMed) (from inception to 1 July 2011), EMBASE (via Ovid) (from inception to 1 July 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2011), and the WHO International Clinical Trials Registry Platform search portal (1 July 2011). In addition, we screened the reference lists of relevant trials or reviews.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that compared the efficacy and safety, or both of TOR with TAM in women with advanced breast cancer. Trials that provided sufficient data on one of the following items: objective response rate (ORR), time to progression (TTP), overall survival (OS), and adverse events, were considered eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Studies were assessed for eligibility and quality. Two review authors independently extracted the following details: first author, publication year, country, years of follow-up, treatment arms, intention-to-treat (ITT) population size, menopausal status of patients, hormone receptor status, response criteria, efficacy and safety outcomes of TOR and TAM arms. Hazard ratios (HR) were derived for time-to-event outcomes, where possible, and response and adverse events were analysed as dichotomous variables. We used a fixed-effect model for meta-analysis unless there was significant between-study heterogeneity.
MAIN RESULTS
A total of 2061 patients from seven RCTs were included for final analysis, with 1226 patients in the TOR group and 835 patients in the TAM group. The ORR for the TOR group was 25.8% (316/1226) whereas, the ORR for the TAM group was 26.9% (225/835). The pooled risk ratio (RR) suggested that the ORRs were not statistically different between the two groups (RR 1.02, 95% confidence interval (CI) 0.88 to 1.18, P = 0.83). The median TTP was 6.1 months for the TOR group and 5.8 months for the TAM group. The median OS was 27.8 months for the TOR group and 27.6 months for the TAM group. There were no significant differences in TTP and OS between the two therapeutic groups (for TTP: HR 1.08, 95% CI 0.94 to 1.24; for OS: HR 1.02, 95% CI 0.86 to 1.20). The frequencies of most adverse events were also similar in the two groups, while headache seemed to occur less in the TOR group than in the TAM group (RR 0.14, 95% CI 0.03 to 0.74, P = 0.02). There was no significant heterogeneity between studies in most of the above meta-analyses. Sensitivity analysis did not alter the results.
AUTHORS' CONCLUSIONS
TOR and TAM are equally effective and the safety profile of the former is at least not worse than the latter in the first-line treatment of patients with advanced breast cancer. Thus, TOR may serve as a reasonable alternative to TAM when anti-oestrogens are applicable but TAM is not the preferred choice for some reason.
Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Randomized Controlled Trials as Topic; Tamoxifen; Toremifene
PubMed: 22786516
DOI: 10.1002/14651858.CD008926.pub2 -
BMC Cancer Jul 2021Tamoxifen (TAM) and Toremifene (TOR), two kinds of selective estrogen receptor modulators (SERMs), have equal efficacy in breast cancer patients. However, TAM has been...
BACKGROUND
Tamoxifen (TAM) and Toremifene (TOR), two kinds of selective estrogen receptor modulators (SERMs), have equal efficacy in breast cancer patients. However, TAM has been proved to affect serum lipid profiles and cause fatty liver disease. The study aimed to compare the effects of TAM and TOR on fatty liver development and lipid profiles.
METHODS
This study performed a retrospective analysis of 308 SERMs-treated early breast cancer patients who were matched 1:1 based on propensity scores. The follow-up period was 3 years. The primary outcomes were fatty liver detected by ultrasonography or computed tomography (CT), variation in fibrosis indexes, and serum lipid profiles change.
RESULTS
The cumulative incidence rate of new-onset fatty liver was higher in the TAM group than in the TOR group (113.2 vs. 67.2 per 1000 person-years, p < 0.001), and more severe fatty livers occurred in the TAM group (25.5 vs. 7.5 per 1000 person-years, p = 0.003). According to the Kaplan-Meier curves, TAM significantly increased the risk of new-onset fatty liver (25.97% vs. 17.53%, p = 0.0243) and the severe fatty liver (5.84% vs. 1.95%, p = 0.0429). TOR decreased the risk of new-onset fatty liver by 45% (hazard ratio = 0.55, p = 0.020) and showed lower fibrotic burden, independent of obesity, lipid, and liver enzyme levels. TOR increased triglycerides less than TAM, and TOR increased high-density lipoprotein cholesterol, while TAM did the opposite. No significant differences in total cholesterol and low-density lipoprotein cholesterol are observed between the two groups.
CONCLUSIONS
TAM treatment is significantly associated with more severe fatty liver disease and liver fibrosis, while TOR is associated with an overall improvement in lipid profiles, which supports continuous monitoring of liver imaging and serum lipid levels during SERM treatment.
Topics: Adult; Breast Neoplasms; Fatty Liver; Female; Humans; Lipids; Middle Aged; Retrospective Studies; Tamoxifen; Toremifene
PubMed: 34246237
DOI: 10.1186/s12885-021-08538-5 -
Cell Discovery 2020Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead...
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the "" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.
PubMed: 32194980
DOI: 10.1038/s41421-020-0153-3