-
Scientific Reports Mar 2021Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase...
Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase inhibitors remain the mainstay of treatment. This study aimed at investigating the antitumor potential of the most potent compounds in citrus peels on breast cancer by exploring their anti-estrogenic and anti-aromatase activities. The ethanolic extract of different varieties of citrus peels along with eight isolated flavonoids were screened against estrogen-dependent breast cancer cell lines besides normal cells for evaluating their safety profile. Naringenin, naringin and quercetin demonstrated the lowest IC and were therefore selected for further assays. In silico molecular modeling against ER and aromatase was performed for the three compounds. In vivo estrogenic and anti-estrogenic assays confirmed an anti-estrogenic activity for the isolates. Moreover, naringenin, naringin and quercetin demonstrated in vitro inhibitory potential against aromatase enzyme along with anticancer potential in vivo, as evidenced by decreased tumor volumes. Reduction in aromatase levels in solid tumors was also observed in treated groups. Overall, this study suggests an antitumor potential for naringenin, naringin and quercetin isolated from citrus peels in breast cancer via possible modulation of estrogen signaling and aromatase inhibition suggesting their use in pre- and post-menopausal breast cancer patients, respectively.
Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Citrus; Estrogen Receptor Modulators; Female; Humans; Mice; Plant Extracts; Xenograft Model Antitumor Assays
PubMed: 33782546
DOI: 10.1038/s41598-021-86599-z -
Current Topics in Medicinal Chemistry 2022Medicinal plants have a long history of use as food and remedy in traditional and modern societies. They have been used as herbal drugs and sources of novel bioactive... (Review)
Review
Medicinal plants have a long history of use as food and remedy in traditional and modern societies. They have been used as herbal drugs and sources of novel bioactive compounds. They provide a wide array of chemical compounds, many of which can not be synthesized via current synthesis methods. Natural products may provide aromatase inhibitory activity through various pathways and may act clinically effective for treating pathologies associated with excessive aromatase secretion, including breast, ovarian, and endometrial cancers, endometriosis, uterine fibroid, benign prostatic hyperplasia (BPH), prostate cancer, infertility, and gynecomastia. Recent studies have shown that natural products with aromatase inhibitory activity can also be good options against secondary recurrence of breast cancer by exhibiting chemopreventive effects. Therefore, screening for new plant-based aromatase inhibitors may provide novel leads for drug discovery and development, particularly with increased clinical efficacy and decreased side effects.
Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Female; Hormones; Humans; Male; Phytochemicals; Prostatic Hyperplasia
PubMed: 34844542
DOI: 10.2174/1568026621666211129141631 -
Histochemistry and Cell Biology Nov 2023This study was conducted to demonstrate the possible protective and therapeutic effects of naringenin, an estrogenically effective flavonoid, in experimental autoimmune...
This study was conducted to demonstrate the possible protective and therapeutic effects of naringenin, an estrogenically effective flavonoid, in experimental autoimmune encephalomyelitis (EAE), which is the rodent model of multiple sclerosis. For this purpose, 50 12-week-old C57BL6 male mice were divided into five groups; control, naringenin, EAE, prophylactic naringenin + EAE, and EAE + therapeutic naringenin. The EAE model was induced with myelin oligodendrocyte glycoprotein, and naringenin (50 mg/kg) was administered by oral gavage. The prophylactic and therapeutic effects of naringenin were examined according to clinical, histopathological, immunohistochemical, electron microscopic, and RT-PCR (aromatase, 3βHSD, estrogen receptors, and progesterone receptor expression) parameters. The acute EAE model was successfully induced, along with its clinical and histopathological findings. RT-PCR showed that expression of aromatase, 3βHSD, estrogen receptor-β, and progesterone receptor gene decreased, while estrogen receptor-α increased after EAE induction. Electron microscopic analysis showed mitochondrial damage and degenerative changes in myelinated axons and neurons in EAE, which could be behind the downregulation in the expressions of neurosteroid enzymes. Aromatase immunopositivity rates also decreased in EAE, while estrogen receptor α and β, and progesterone receptor immunopositivity rates increased. Naringenin improved aromatase immunopositivity rates and gene expression in both prophylactic and therapeutic use. Clinical and histopathological findings revealed that EAE findings were alleviated in both prophylactic and therapeutic groups, along with significantly decreased inflammatory cell infiltrations in the white matter of the spinal cords. In conclusion, naringenin could provide long-term beneficial effects even in prophylactic use due to stimulating aromatase expression, but it could not prevent or eliminate the EAE model's lesions completely.
Topics: Male; Animals; Mice; Encephalomyelitis, Autoimmune, Experimental; Receptors, Progesterone; Receptors, Estrogen; Aromatase; Mice, Inbred C57BL; Spinal Cord
PubMed: 37378907
DOI: 10.1007/s00418-023-02217-1 -
Nutrients Oct 2022Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme,...
Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme, 17-alpha-hydroxylase (Cyp17a1) expression. It has been demonstrated that Kelulut honey (KH) improves both female and male reproductive system anomalies in animal studies. Here, we examined the effects of isolated and combined KH, metformin, and clomiphene in improving folliculogenesis, aromatase, and steroidogenic enzyme profiles and ovarian histomorphology in letrozole-induced PCOS rats. Letrozole (1 mg/kg/day) was administered to female Sprague-Dawley (SD) rats for 21 days to induce PCOS. PCOS rats were subsequently divided into six experimental groups: untreated, treatment with metformin (500 mg/kg/day), clomiphene (2 mg/kg/day), KH (1 g/kg/day), combined KH (1 g/kg/day) and metformin (500 mg/kg/day), and combined KH (1 g/kg/day) and clomiphene (2 mg/kg/day). All treatments were given orally for 35 days. We found that KH was comparable with clomiphene and metformin in improving the expression of Cyp17a1 and Cyp19a1, apart from enhancing folliculogenesis both histologically and through the expression of folliculogenesis-related genes. Besides, the combination of KH with clomiphene was the most effective treatment in improving the ovarian histomorphology of PCOS rats. The effectiveness of KH in restoring altered folliculogenesis, steroidogenic, and aromatase enzyme profiles in PCOS warrants a future clinical trial to validate its therapeutic effect clinically.
Topics: Animals; Female; Rats; Aromatase; Clomiphene; Honey; Letrozole; Metformin; Polycystic Ovary Syndrome; Rats, Sprague-Dawley
PubMed: 36297046
DOI: 10.3390/nu14204364 -
Molecular Pharmaceutics Jul 2022The abnormal expression of aromatase is associated with the occurrence and development of a variety of neurological diseases and tumors. A series of F-labeled and...
The abnormal expression of aromatase is associated with the occurrence and development of a variety of neurological diseases and tumors. A series of F-labeled and Ga-labeled potential aromatase-binding candidate compounds were designed and synthesized based on the structures of aromatase inhibitors. Competitive inhibition experiments in vitro and molecular docking showed that BIBD-069 and BIBD-071 have high affinity for aromatase. The radiolabeling conditions of [F]BIBD-069 and [F]BIBD-071 were simple, and the yields were high. Biodistribution and in vivo inhibition experiments confirmed that [F]BIBD-069 and [F]BIBD-071 specifically bind to aromatase. [F]BIBD-069 and [F]BIBD-071 selectively imaged the amygdala and nucleus of the stria terminalis, which is similar to the imaging result of [C]vorozole. Radiometabolites of [F]BIBD-069 and [F]BIBD-071 did not bind to aromatase and interfered with brain imaging. MicroPET-CT imaging further confirmed that [F]BIBD-069 and [F]BIBD-071 can specifically bind to aromatase and were not defluorinated in vivo. Given that [F]BIBD-069 and [F]BIBD-071 exhibit excellent aromatase binding affinities, mild radiolabeling conditions, and good pharmacokinetics, they can be important tools for the diagnosis and treatment of aromatase-related diseases.
Topics: Aromatase; Aromatase Inhibitors; Fluorine Radioisotopes; Molecular Docking Simulation; Positron-Emission Tomography; Tissue Distribution
PubMed: 35621695
DOI: 10.1021/acs.molpharmaceut.2c00176 -
Molecules (Basel, Switzerland) Nov 2020The current therapeutic approach for the treatment of hormone dependent breast cancer includes interference with estrogen receptors via either selective modulators or... (Review)
Review
The current therapeutic approach for the treatment of hormone dependent breast cancer includes interference with estrogen receptors via either selective modulators or estrogens deprivation, by preventing their biosynthesis with aromatase inhibitors. Severe side effects and acquired resistance are drawbacks of both drug classes, and the efforts to overcome these issues still allow for research in this field to be animated. This review reports on recent findings that have opened new avenues for reconsidering the role of aromatase enzymes (and estrogen receptors) leading to the possibility of looking at well-known targets in a new perspective.
Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Estrogens; Female; Humans; Molecular Targeted Therapy; Receptors, Estrogen
PubMed: 33207783
DOI: 10.3390/molecules25225351 -
International Journal of Molecular... Jan 2023Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are...
Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer.
Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase () mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of , , and mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment with a variety of histone deacetylase inhibitors (HDACIs) in primary cultures of enriched breast tumor epithelial cells, from MMTV-PyMT mice, resulted in suppression of StAR and E2 levels. Importantly, inhibition of StAR, concomitant with E2 synthesis, by various HDACIs, at clinical and preclinical doses, in MCF7 cells, indicated therapeutic relevance of StAR in hormone-dependent BCs. These findings provide insights into the molecular events underlying the differential expression of StAR in human and mouse cancerous and non-cancerous breast cells/tissues, highlighting StAR could serve not only as a novel diagnostic maker but also as a therapeutic target for the most prevalent hormone-sensitive BCs.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Aromatase; Triple Negative Breast Neoplasms; Estradiol; Mammary Neoplasms, Animal; Mice, Transgenic; RNA, Messenger
PubMed: 36614200
DOI: 10.3390/ijms24010758 -
Journal of Molecular Medicine (Berlin,... Aug 2023Poly(ADP-ribose) polymerase 2 (PARP2) alongside PARP1 are responsible for the bulk of cellular PARP activity, and they were first described as DNA repair factors....
Poly(ADP-ribose) polymerase 2 (PARP2) alongside PARP1 are responsible for the bulk of cellular PARP activity, and they were first described as DNA repair factors. However, research in past decades implicated PARPs in biological functions as diverse as the regulation of cellular energetics, lipid homeostasis, cell death, and inflammation. PARP activation was described in Th2-mediated inflammatory processes, but studies focused on the role of PARP1, while we have little information on PARP2 in inflammatory regulation. In this study, we assessed the role of PARP2 in a Th17-mediated inflammatory skin condition, psoriasis. We found that PARP2 mRNA expression is increased in human psoriatic lesions. Therefore, we studied the functional consequence of decreased PARP2 expression in murine and cellular human models of psoriasis. We observed that the deletion of PARP2 attenuated the imiquimod-induced psoriasis-like dermatitis in mice. Silencing of PARP2 in human keratinocytes prevented their hyperproliferation, maintained their terminal differentiation, and reduced their production of inflammatory mediators after treatment with psoriasis-mimicking cytokines IL17A and TNFα. Underlying these observations, we found that aromatase was induced in the epidermis of PARP2 knock-out mice and in PARP2-deficient human keratinocytes, and the resulting higher estradiol production suppressed NF-κB activation, and hence, inflammation in keratinocytes. Steroidogenic alterations have previously been described in psoriasis, and we extend these observations by showing that aromatase expression is reduced in psoriatic lesions. Collectively, our data identify PARP2 as a modulator of estrogen biosynthesis by epidermal keratinocytes that may be relevant in Th17 type inflammation. KEY MESSAGES : PARP2 mRNA expression is increased in lesional skin of psoriasis patients. PARP2 deletion in mice attenuated IMQ-induced psoriasis-like dermatitis. NF-κB activation is suppressed in PARP2-deficient human keratinocytes. Higher estradiol in PARP2-deficient keratinocytes conveys anti-inflammatory effect.
Topics: Animals; Humans; Mice; Aromatase; Dermatitis; Disease Models, Animal; Imiquimod; Inflammation; Keratinocytes; Mice, Inbred BALB C; NF-kappa B; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Psoriasis; RNA, Messenger; Skin
PubMed: 37351597
DOI: 10.1007/s00109-023-02338-z -
International Journal of Molecular... Dec 2021In addition to being a steroid hormone, 17β-estradiol (E) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans.... (Review)
Review
In addition to being a steroid hormone, 17β-estradiol (E) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E (NDE) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.
Topics: Animals; Aromatase; Estradiol; Female; Humans; Male; Neuronal Plasticity; Neurons; Signal Transduction; Spatial Memory; Synapses
PubMed: 34948039
DOI: 10.3390/ijms222413242 -
Molecular and Cellular Biology Oct 2021Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high levels of estradiol....
Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high levels of estradiol. Aromatase catalyzes estradiol synthesis; however, the factors regulating aromatase activity are unknown. We identified a new 22-kDa protein, aromatase interacting partner in breast (AIPB), from the endoplasmic reticulum of human breast tissue. AIPB expression is reduced in tumorigenic breast and further reduced in triple-negative tumors. Like that of aromatase, AIPB expression is induced by nonsteroidal estrogen. We found that AIPB and aromatase interact in nontumorigenic and tumorigenic breast tissues and cells. In tumorigenic cells, conditional AIPB overexpression decreased estradiol, and blocking AIPB availability with an AIPB-binding antibody increased estradiol. Estradiol synthesis is highly increased in AIPB knockdown cells, suggesting that the newly identified AIPB protein is important for aromatase activity and a key modulator of estradiol synthesis. Thus, a change in AIPB protein expression may represent an early event in tumorigenesis and be predictive of an increased risk of developing breast cancer.
Topics: Amino Acid Sequence; Aromatase; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Endoplasmic Reticulum; Estradiol; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Neoplasm Proteins; Progesterone; RNA Interference; RNA, Small Interfering
PubMed: 34460330
DOI: 10.1128/MCB.00357-21