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Molecules (Basel, Switzerland) Mar 2021The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been... (Review)
Review
The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings. The developments of the last five years in the search for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity against different kinases and antiproliferative activity.
Topics: Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors
PubMed: 33803309
DOI: 10.3390/molecules26051488 -
RSC Medicinal Chemistry Feb 2023Aromatase (CYP19A1) inhibitors are the mainstay therapeutics for the treatment of hormone dependant breast cancer, which accounts for approximately 70% of all breast...
Aromatase (CYP19A1) inhibitors are the mainstay therapeutics for the treatment of hormone dependant breast cancer, which accounts for approximately 70% of all breast cancer cases. However, increased resistance to the clinically used aromatase inhibitors, including letrozole and anastrazole, and off target effects, necessitates the development of aromatase inhibitors with improved drug profiles. The development of extended 4th generation pyridine based aromatase inhibitors with dual binding (haem and access channel) is therefore of interest and here we describe the design, synthesis and computational studies. Cytotoxicity and selectivity studies identified the pyridine derivative (4-bromophenyl)(6-(but-2-yn-1-yloxy)benzofuran-2-yl)(pyridin-3-yl)methanol (10c) as optimal with CYP19A1 IC 0.83 nM ( letrozole IC 0.70 nM), and an excellent cytotoxicity and selectivity profile. Interestingly, computational studies for the 6--butynyloxy (10) and 6--pentynyloxy (11) derivatives identified an alternative access channel lined by Phe221, Trp224, Gln225 and Leu477, providing further insight into the potential binding mode and interactions of the non-steroidal aromatase inhibitors.
PubMed: 36846364
DOI: 10.1039/d2md00352j -
Journal of Endocrinological... Mar 2023The aim of this review is to discuss the role of androgens in the progression of endometrial carcinoma (EC) with particular focus on the different kinds of androgenic... (Review)
Review
PURPOSE
The aim of this review is to discuss the role of androgens in the progression of endometrial carcinoma (EC) with particular focus on the different kinds of androgenic hormones, androgen receptor (AR) and intracrine androgen metabolism.
METHODS
A comprehensive literature search within PubMed was performed. Selected publications related to androgens and EC were reviewed.
RESULTS
There are different kinds of androgenic hormones, and different kinds of androgens may have different effects. Elevated androgens (especially testosterone) have been associated with an increased EC risk in postmenopausal women. 5α-reductases (5α-Reds) and 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) pathway may inhibit the progression of EC mediated by dihydrotestosterone (DHT), but aromatases stimulate further progression of EC. The most of studies accessing the prognostic value of AR have found that AR expression may be a favorable prognostic indicator.
CONCLUSION
Androgens may have both oncogenic and tumor suppressive roles. Androgen-specific biases in metabolism and the expression of AR may contribute to the different prognosis of patients with EC.
Topics: Humans; Female; Androgens; Dihydrotestosterone; Endometrial Neoplasms; Receptors, Androgen; Testosterone
PubMed: 36583833
DOI: 10.1007/s40618-022-01916-1 -
Iranian Journal of Basic Medical... Dec 2019Kisspeptin and opioids are important factors for controlling GnRH/LH secretion. In present study, influences of kisspeptin or morphine were investigated on 5α-...
OBJECTIVES
Kisspeptin and opioids are important factors for controlling GnRH/LH secretion. In present study, influences of kisspeptin or morphine were investigated on 5α- reductase or aromatase () genes expression in the hypothalamus, testis and liver. It aimed to investigate whether kisspeptin pathway may control morphine effects on plasma concentration of testosterone.
MATERIALS AND METHODS
Twenty adult male rats in four groups received saline/saline, kisspeptin (1 nmol)/saline, morphine (5 mg/kg)/saline or kisspeptin/morphine respectively. Mean relative 5α-reductase and aromatase mRNA levels were determined by RT-PCR.
RESULTS
Morphine/saline injection increased significantly mean relative mRNA levels of hypothalamic 5α-reductase or aromatase compared to saline/saline. While morphine/saline did not alter mRNA levels of them compared to saline/saline group in the testis and liver. Kisspeptin/saline did not significantly decrease mean relative 5α-reductase or aromatase genes expression compared to saline/saline group in the hypothalamus, testis and liver. Injections of kisspeptin/morphine did not significantly decrease mean relative 5α-reductase or genes expression compared to morphine/saline group.
CONCLUSION
Up-regulation of hypothalamic 5α-reductase or aromatase mRNA levels may partly induce the inhibitory effects of morphine on GnRH/LH release. Different effects of morphine on aromatase or 5α- reductase genes expression levels in the liver and testis compared to brain may be partly due to different sensitivity or functions of them to morphine used dose.
PubMed: 32133065
DOI: 10.22038/IJBMS.2019.14053 -
Biology of Sex Differences Oct 2023Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens...
BACKGROUND
Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response.
METHODS
We performed several consecutive studies in adult Sprague-Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference).
RESULTS
The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs.
CONCLUSIONS
The present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.
Topics: Rats; Female; Male; Animals; Ketamine; Aromatase; Depression; Letrozole; Sex Characteristics; Rats, Sprague-Dawley; Antidepressive Agents; Estrogens
PubMed: 37876000
DOI: 10.1186/s13293-023-00560-5 -
Oxidative Medicine and Cellular... 2021Aromatase is a key enzyme in the transformation of androgen into estrogen. Its high expression will destroy the hormonal balance in the male body, and the excessive... (Review)
Review
Aromatase is a key enzyme in the transformation of androgen into estrogen. Its high expression will destroy the hormonal balance in the male body, and the excessive transformation of androgen into estrogen in the body will further damage the spermatogenic function of the testis, affect the normal development of the sperm, and cause spermatogenic disturbance. Adipose tissue has a high expression of aromatase and shows high enzymatic activity and ability to convert estrogen. Adipose tissue is the most estrogen-producing nongonadal tissue in the body because of its large size, accounting for about 20% of the body mass in healthy adults. PPAR is recognized as the key adipose differentiation in the transcriptional regulation of the transcription factor. In the process of adipocyte differentiation, PPAR regulate the expression of aromatase. The increase of aromatase is associated with the inflammatory response in adipose tissue caused by obesity. After obesity, the increase of proinflammatory factors in adipocytes will lead to enhanced transcription of the CYP19 gene encoding aromatase in adipocytes, which in turn will lead to increased expression of aromatase in adipocytes. This article reviews the regulation of male sterility from the angle of the "obesity-inflammation-aromatase" axis.
Topics: Animals; Aromatase; Biomedical Research; Humans; Infertility, Male; Inflammation; Male; Models, Biological; Obesity
PubMed: 33628365
DOI: 10.1155/2021/6612796 -
Endocrinology Oct 2020The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that...
The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol in the testis and brain of male mice. Estradiol formation was shown to regulate sexual activity in various species, but the relative contributions to sexual behavior of estrogen that arises in the brain versus from the gonads remained unclear. To determine the role of brain aromatase in regulating male sexual activity, we generated a brain-specific aromatase knockout (bArKO) mouse. A newly generated whole-body total aromatase knockout mouse of the same genetic background served as a positive control. Here we demonstrate that local aromatase expression and estrogen production in the brain is partially required for male sexual behavior and sex hormone homeostasis. Male bArKO mice exhibited decreased sexual activity in the presence of strikingly elevated circulating testosterone. In castrated adult bArKO mice, administration of testosterone only partially restored sexual behavior; full sexual behavior, however, was achieved only when both estradiol and testosterone were administered together. Thus, aromatase in the brain is, in part, necessary for testosterone-dependent male sexual activity. We also found that brain aromatase is required for negative feedback regulation of circulating testosterone of testicular origin. Our findings suggest testosterone activates male sexual behavior in part via conversion to estradiol in the brain. These studies provide foundational evidence that sexual behavior may be modified through inhibition or enhancement of brain aromatase enzyme activity and/or utilization of selective estrogen receptor modulators.
Topics: Animals; Aromatase; Aromatase Inhibitors; Brain; Cells, Cultured; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse Embryonic Stem Cells; Sex Characteristics; Sexual Behavior, Animal; Testis
PubMed: 32910181
DOI: 10.1210/endocr/bqaa137 -
American Journal of Physiology. Renal... Sep 2022Aromatase is a monooxygenase that catalyzes the rate-limiting step of estrogen biosynthesis from androgens. Aromatase inhibitors are widely used for the treatment of...
Aromatase is a monooxygenase that catalyzes the rate-limiting step of estrogen biosynthesis from androgens. Aromatase inhibitors are widely used for the treatment of patients with hormone receptor-positive breast cancer. However, the effects of aromatase inhibitors on cardiovascular and renal health in females are understudied. Given that estrogen is protective against cardiovascular and kidney diseases, we hypothesized that aromatase inhibition elevates blood pressure and induces kidney injury in female Sprague-Dawley rats. Twelve-week-old female rats were implanted with radiotelemetry transmitters to continuously monitor blood pressure. After baseline blood pressure recording, rats were randomly assigned to treatment with the aromatase inhibitor anastrozole (ASZ) or vehicle (Veh) in drinking water. Twenty days after treatment initiation, rats were shifted from a normal-salt (NS) diet to a high-salt (HS) diet for an additional 40 days. Rats were euthanized 60 days after treatment initiation. Body weight increased in both groups over the study period, but the increase was greater in the ASZ-treated group than in the Veh-treated group. Mean arterial pressure increased in ASZ-treated rats during the NS and HS diet phases but remained unchanged in Veh-treated rats. In addition, urinary excretion of albumin and kidney injury marker-1 and plasma urea were increased in response to aromatase inhibition. Furthermore, histological assessment revealed that ASZ treatment increased morphological evidence of renal tubular injury and proximal tubular brush border loss. In conclusion, chronic aromatase inhibition in vivo with ASZ increases blood pressure and markers of renal proximal tubular injury in female Sprague-Dawley rats, suggesting an important role for aromatization in the maintenance cardiovascular and renal health in females. Aromatase enzyme catalyzes the rate-limiting step in estrogen biosynthesis. Aromatase inhibitors are clinically used for the treatment of patients with breast cancer; however, the impact of inhibiting aromatization on blood pressure and renal function is incompletely understood. The present findings demonstrate that systemic anastrozole treatment increases blood pressure and renal tubular injury markers in female rats fed a high-salt diet, suggesting an important role for aromatization in preserving cardiovascular and renal health in females.
Topics: Anastrozole; Animals; Aromatase Inhibitors; Biomarkers; Blood Pressure; Estrogens; Female; Hypertension; Kidney; Neoplasms; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary
PubMed: 35900340
DOI: 10.1152/ajprenal.00055.2022 -
Turkish Journal of Pharmaceutical... Dec 2022Aromatase is an enzyme that catalyzes the conversion of androgens to estrogens. While inhibition of aromatase is a useful approach for treating breast cancer, it may...
OBJECTIVES
Aromatase is an enzyme that catalyzes the conversion of androgens to estrogens. While inhibition of aromatase is a useful approach for treating breast cancer, it may also have toxicological consequences due to its endocrine disrupting/modulating effect. In this study, sensitivity and performance of two assays -a cell free and a cell-based- for evaluating aromatase activity were investigated by testing known aromatase inhibitors and partial validation of the methods was performed. Advantages and disadvantages of these methods are also discussed.
MATERIALS AND METHODS
Aromatase activity was evaluated two models; direct measurement with a cell-free assay using a fluorescent substrate and recombinant human enzyme and indirect evaluation with a cell-based assay where cell proliferation was determined in estrogen receptor positive human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone.
RESULTS
In the cell-free direct measurement assay, reference compounds ketoconazole and aminoglutethimide have been shown to inhibit the aromatase enzyme with half-maximal inhibitory concentration (IC) values concordant with literature. In cell-based indirect measurement assay, only ketoconazole dose-dependently inhibited cell proliferation with 3.47 x 10 M IC. Inter-assay and intra-assay reproducibility of both methods was found to be within acceptable deviation levels.
CONCLUSION
Both methods can be successfully applied. However, to evaluate the potential aromatase activity of the novel compounds , it seems better to perform both the cell-based and the cell-free assays that allows low-moderate biotransformation and eliminate cytotoxicity potential, respectively.
PubMed: 36544280
DOI: 10.4274/tjps.galenos.2021.85530 -
The Journal of Steroid Biochemistry and... Dec 2019Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via...
Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.
Topics: Aromatase; Cells, Cultured; Citalopram; Female; Fluoxetine; Humans; Molecular Docking Simulation; Paroxetine; Placenta; Pregnancy; Serotonin; Selective Serotonin Reuptake Inhibitors; Sertraline; Trophoblasts; Venlafaxine Hydrochloride
PubMed: 31509772
DOI: 10.1016/j.jsbmb.2019.105470