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Breast Cancer Research and Treatment Sep 2023Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast...
PURPOSE
Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation.
METHODS
We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis.
RESULTS
There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40-1.03; P = 0.07).
CONCLUSION
Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.
Topics: Humans; Female; Tamoxifen; Breast Neoplasms; Raloxifene Hydrochloride; Genes, BRCA1; Mutation; Risk Factors; BRCA1 Protein; BRCA2 Protein
PubMed: 37432545
DOI: 10.1007/s10549-023-06991-3 -
Biochemical and Biophysical Research... Sep 2023Atherosclerosis, a leading cause of cardiovascular disease, remains a significant global health concern. Tamoxifen and raloxifene, selective estrogen receptor modulators...
Cardioprotective effect of tamoxifen and raloxifene: Preventing proteoglycan synthesis by modulating non-canonical TGF-β signalling through NADPH oxidase and ERK phosphorylation.
Atherosclerosis, a leading cause of cardiovascular disease, remains a significant global health concern. Tamoxifen and raloxifene, selective estrogen receptor modulators (SERMs), have demonstrated potential cardioprotective effects. However, the underlying molecular mechanisms by which these SERMs modulate Transforming Growth Factor-β (TGF-β) signaling in human vascular smooth muscle cells (VSMCs) remain largely unexplored. This study sought to investigate the impact of tamoxifen and raloxifene on TGF-β-induced CHSY1 expression and Smad2 linker region phosphorylation in VSMCs and to elucidate the role of reactive oxygen species (ROS), NADPH oxidase (NOX), and kinase pathways in mediating these effects. Employing a comprehensive experimental strategy, VSMCs were treated with TGF-β in the presence or absence of tamoxifen, raloxifene, and various pharmacological inhibitors. Subsequently, CHSY1 mRNA expression, Smad2C and Smad2L phosphorylation, ROS production, p47phox and ERK 1/2 phosphorylation were assessed. Our results revealed that tamoxifen and raloxifene significantly attenuated TGF-β-mediated CHSY1 mRNA expression and Smad2 linker region phosphorylation, without affecting the canonical TGF-β-Smad2C pathway. Furthermore, these compounds effectively inhibited ROS production, p47phox and ERK 1/2 phosphorylation, implicating the involvement of the TGF-β-NOX-ERK-Smad2L signaling cascade in their cardioprotective properties. This study provides a comprehensive understanding of the molecular mechanisms underlying the cardioprotective effects of tamoxifen and raloxifene in VSMCs, offering valuable insights for the development of targeted therapeutic strategies aimed at atherosclerosis prevention and the promotion of cardiovascular health.
Topics: Humans; Phosphorylation; Transforming Growth Factor beta; Raloxifene Hydrochloride; Reactive Oxygen Species; Tamoxifen; Selective Estrogen Receptor Modulators; Proteoglycans; Atherosclerosis; NADPH Oxidases; RNA, Messenger
PubMed: 37307710
DOI: 10.1016/j.bbrc.2023.06.031 -
Bioanalysis Jun 2023A reliable, sensitive, HPLC method was developed and validated to simultaneously quantify raloxifene (RLX) and cladrin (CLD). The C18 column was used to analyze RLX...
A reliable, sensitive, HPLC method was developed and validated to simultaneously quantify raloxifene (RLX) and cladrin (CLD). The C18 column was used to analyze RLX and CLD at λ 285 and 249 nm. The mobile phase was composed of acetonitrile and 35:65% v/v aqueous solution of 0.1% formic acid. The method was linear over the linearity range of 0.078-20 μg/ml, and the limit of detection and limit of quantification for RLX and CLD were 0.191 and 0.228 and 0.581 and 0.69 μg/ml, respectively. In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines, the developed method is precise and accurate for simultaneous estimation of RLX and CLD with applications in liver microsomal stability in mice, rabbits, dogs, monkeys and humans.
Topics: Mice; Humans; Animals; Dogs; Rabbits; Chromatography, High Pressure Liquid; Raloxifene Hydrochloride; Isoflavones
PubMed: 37254752
DOI: 10.4155/bio-2023-0046 -
Bone Aug 2023Raloxifene (RAL) reduces clinical fracture risk despite modest effects on bone mass and density. This reduction in fracture risk may be due to improved material...
Raloxifene (RAL) reduces clinical fracture risk despite modest effects on bone mass and density. This reduction in fracture risk may be due to improved material level-mechanical properties through a non-cell mediated increase in bone hydration. Synthetic salmon calcitonin (CAL) has also demonstrated efficacy in reducing fracture risk with only modest bone mass and density improvements. This study aimed to determine if CAL could modify healthy and diseased bone through cell-independent mechanisms that alter hydration similar to RAL. 26-week-old male C57BL/6 mice induced with chronic kidney disease (CKD) beginning at 16 weeks of age via 0.2 % adenine-laced casein-based (0.9 % P, 0.6 % C) chow, and their non-CKD control littermates (Con), were utilized. Upon sacrifice, right femora were randomly assigned to the following ex vivo experimental groups: RAL (2 μM, n = 10 CKD, n = 10 Con), CAL (100 nM, n = 10 CKD, n = 10 Con), or Vehicle (VEH; n = 9 CKD, n = 9 Con). Bones were incubated in PBS + drug solution at 37 °C for 14 days using an established ex vivo soaking methodology. Cortical geometry (μCT) was used to confirm a CKD bone phenotype, including porosity and cortical thinning, at sacrifice. Femora were assessed for mechanical properties (3-point bending) and bone hydration (via solid state nuclear magnetic resonance spectroscopy with magic angle spinning (ssNMR)). Data were analyzed by two-tailed t-tests (μCT) or 2-way ANOVA for main effects of disease, treatment, and their interaction. Tukey's post hoc analyses followed a significant main effect of treatment to determine the source of the effect. Imaging confirmed a cortical phenotype reflective of CKD, including lower cortical thickness (p < 0.0001) and increased cortical porosity (p = 0.02) compared to Con. In addition, CKD resulted in weaker, less deformable bones. In CKD bones, ex vivo exposure to RAL or CAL improved total work (+120 % and +107 %, respectively; p < 0.05), post-yield work (+143 % and +133 %), total displacement (+197 % and +229 %), total strain (+225 % and +243 %), and toughness (+158 % and +119 %) vs. CKD VEH soaked bones. Ex vivo exposure to RAL or CAL did not impact any mechanical properties in Con bone. Matrix-bound water by ssNMR showed CAL treated bones had significantly higher bound water compared to VEH treated bones in both CKD and Con cohorts (p = 0.001 and p = 0.01, respectively). RAL positively modulated bound water in CKD bone compared to VEH (p = 0.002) but not in Con bone. There were no significant differences between bones soaked with CAL vs. RAL for any outcomes measured. RAL and CAL improve important post-yield properties and toughness in a non-cell mediated manner in CKD bone but not in Con bones. While RAL treated CKD bones had higher matrix-bound water content in line with previous reports, both Con and CKD bones exposed to CAL had higher matrix-bound water. Therapeutic modulation of water, specifically the bound water fraction, represents a novel approach to improving mechanical properties and potentially reducing fracture risk.
Topics: Animals; Male; Mice; Bone Density Conservation Agents; Calcitonin; Fractures, Bone; Mice, Inbred C57BL; Raloxifene Hydrochloride; Water
PubMed: 37196853
DOI: 10.1016/j.bone.2023.116805 -
International Journal of Biological... Jul 2023Cyclophosphamide (CP) is one of the most widely used anticancer drugs for various malignancies. However, its long-term use leads to ALDH1A1-mediated inactivation and...
Cyclophosphamide (CP) is one of the most widely used anticancer drugs for various malignancies. However, its long-term use leads to ALDH1A1-mediated inactivation and subsequent resistance which necessitates the development of potential ALDH1A1 inhibitors. Currently, ALDH1A1 inhibitors from different chemical classes have been reported, but these failed to reach the market due to safety and efficacy problems. Developing a new treatment from the ground requires a huge amount of time, effort, and money, therefore it is worthwhile to improve CP efficacy by proposing better adjuvants as ALDH1A1 inhibitors. Herein, the database constituting the FDA-approved drugs with well-established safety and toxicity profiles was screened through already reported machine learning models by our research group. This model is validated for discriminating the ALDH1A1 inhibitors and non-inhibitors. Virtual screening protocol (VS) from this model identified four FDA-approved drugs, raloxifene, bazedoxifene, avanafil, and betrixaban as selective ALDH1A1 inhibitors. The molecular docking, dynamics, and water swap analysis also suggested these drugs to be promising ALDH1A1 inhibitors which were further validated for their CP resistance reversal potential by in-vitro analysis. The in-vitro enzymatic assay results indicated that raloxifene and bazedoxifene selectively inhibited the ALDH1A1 enzyme with IC values of 2.35 and 4.41 μM respectively, whereas IC values of both the drugs against ALDH2 and ALDH3A1 was >100 μM. Additional in-vitro studies with well-reported ALDH1A1 overexpressing A549 and MIA paCa-2 cell lines suggested that mafosfamide sensitivity was further ameliorated by the combination of both raloxifene and bazedoxifene. Collectively, in-silico and in-vitro studies indicate raloxifene and bazedoxifene act as promising adjuvants with CP that may improve the quality of treatment for cancer patients with minimal toxicities.
Topics: Humans; Raloxifene Hydrochloride; Molecular Docking Simulation; Drug Repositioning; Cyclophosphamide; Neoplasms; Aldehyde Dehydrogenase, Mitochondrial; Aldehyde Dehydrogenase 1 Family; Retinal Dehydrogenase
PubMed: 37160174
DOI: 10.1016/j.ijbiomac.2023.124749 -
Journal of Clinical Oncology : Official... Jun 2023Journal Journal of Clinical OncologyPatients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer... (Review)
Review
Journal Journal of Clinical OncologyPatients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer improved survival, thus the side effects of primary/secondary prevention must be considered relative to the benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing in the setting of secondary prevention.
Topics: Female; Humans; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Secondary Prevention; Tamoxifen; Raloxifene Hydrochloride
PubMed: 37126767
DOI: 10.1200/JCO.23.00455 -
Schizophrenia Bulletin Nov 2023Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND HYPOTHESIS
Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD.
STUDY DESIGN
This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models.
STUDY RESULTS
We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups.
CONCLUSIONS
Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.
Topics: Adult; Male; Female; Humans; Infant, Newborn; Raloxifene Hydrochloride; Schizophrenia; Antipsychotic Agents; Postmenopause; Selective Estrogen Receptor Modulators; Double-Blind Method; Treatment Outcome
PubMed: 37116866
DOI: 10.1093/schbul/sbad058 -
In Vivo (Athens, Greece) 2023Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination...
BACKGROUND/AIM
Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve the response of the patients to therapy in several cancers. The aim of the present study was to merge these two strategies and evaluate whether the two-drug- or three-drug- combination of sorafenib, raloxifene, and loratadine improves the antineoplastic effect on human liver cancer cells in comparison to the single-drug effect.
MATERIALS AND METHODS
The human liver cancer cell lines HepG2 and HuH7 were studied. The effect of sorafenib, raloxifene, and loratadine on the metabolic activity was determined using the MTT assay. The inhibitory concentrations (IC and IC) were calculated from these results and used in the drug-combination experiments. Apoptosis and cell survival were studied by flow cytometry and using the colony formation assay, respectively.
RESULTS
In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations.
CONCLUSION
The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients.
Topics: Humans; Sorafenib; Loratadine; Raloxifene Hydrochloride; Carcinoma, Hepatocellular; Cell Proliferation; Liver Neoplasms; Antineoplastic Agents; Apoptosis; Cell Line, Tumor
PubMed: 37103074
DOI: 10.21873/invivo.13190 -
Biomedical Chromatography : BMC Aug 2023A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles....
Quality by design-steered development and validation of analytical and bioanalytical methods for raloxifene: Application of Monte Carlo simulations and variance inflation factor.
A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles. Factor screening studies, employing Taguchi design, indicated buffer volume percentage and isocratic flow rate as the critical method parameters (CMPs), which significantly influence the chosen critical analytical attributes, that is, tailing factor and theoretical plate number. Method conditions were subsequently optimized using face-centered cubic design with magnitude of variance inflation factor for assessing multicollinearity among CMPs. Method operable design region (MODR) was earmarked and liquid chromatographic separation optimized using 0.05 M citrate buffer, acetonitrile, and methanol (57:40:3 v/v/v) as ggmobile phase at 0.9 mL min flow rate, λ of 280 nm, and column temperature of 40°C. Validation of the developed analytical method was accomplished as per International Council on Harmonization (ICH) guidelines confirming high levels of linearity, precision, accuracy, robustness, and sensitivity. Application of Monte Carlo simulations enabled the attainment of best plausible chromatographic resolution and corroboration of the demarcated MODR. Establishment and validation of the bioanalytical method using rat plasma samples, along with forced degradation and stability studies, corroborated the aptness of developed HPLC methods for drug quantification in the biological fluids, as well as in bulk and marketed dosage forms.
Topics: Animals; Rats; Raloxifene Hydrochloride; Monte Carlo Method; Reproducibility of Results; Limit of Detection; Chromatography, Liquid; Chromatography, High Pressure Liquid
PubMed: 37041119
DOI: 10.1002/bmc.5641 -
Calcified Tissue International Jun 2023To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen... (Meta-Analysis)
Meta-Analysis Review
The Clinical Effectiveness of Denosumab (Prolia®) for the Treatment of Osteoporosis in Postmenopausal Women, Compared to Bisphosphonates, Selective Estrogen Receptor Modulators (SERM), and Placebo: A Systematic Review and Network Meta-Analysis.
To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs; bazedoxifene, raloxifene) or placebo, for the treatment of osteoporosis in postmenopausal women (PMW). Systematic searches were run in PubMed, Embase & Cochrane Library on 27-April-2022. Randomized controlled trials (RCTs) that included osteoporotic PMW allocated to denosumab, SERMs, bisphosphonates, or placebo were eligible for inclusion. RCTs were appraised using Cochrane Risk of Bias 2.0. Bayesian network and/or pairwise meta-analyses were conducted on predetermined outcomes (i.e. vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, adverse events [AEs], serious AEs (SAEs), withdrawals due to AEs, AEs caused by denosumab discontinuation). A total of 12 RCTs (k = 22 publications; n = 25,879 participants) were included in the analyses. Denosumab, reported a statistically significant increase in lumbar spine (LS) and total hip (TH) BMD, compared to placebo. Similarly, denosumab also resulted in a statistically significant increase in TH BMD compared to the raloxifene and bazedoxifene. However, relative to denosumab, alendronate, ibandronate and risedronate resulted in significant improvements in both femoral neck (FN) and LS BMD. With regards to vertebral fractures and all safety outcomes, there were no statistically significant differences between denosumab and any of the comparator. Relative to placebo, denosumab was associated with significant benefits in both LS and TH BMD. Additionally, denosumab (compared to placebo) was not associated with reductions in vertebral and nonvertebral fractures. Finally, denosumab was not associated with improvement in safety outcomes, compared to placebo. These findings should be interpreted with caution as some analyses suffered from statistical imprecision.
Topics: Female; Humans; Diphosphonates; Selective Estrogen Receptor Modulators; Denosumab; Alendronate; Bone Density Conservation Agents; Risedronic Acid; Raloxifene Hydrochloride; Ibandronic Acid; Network Meta-Analysis; Postmenopause; Osteoporosis, Postmenopausal; Osteoporosis; Bone Density; Spinal Fractures; Treatment Outcome
PubMed: 37016189
DOI: 10.1007/s00223-023-01078-z