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Mini Reviews in Medicinal Chemistry 2021Breast cancer is the most frequently diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an... (Review)
Review
Breast cancer is the most frequently diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly, estradiol plays a significant role in the initiation and development of hormone-dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate, and estrone-sulfate also play an important role as precursors for estrogen biosynthesis. Estrogen deprivation exhibits an attractive phenomenon in the advancement of ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as an attractive therapy for the treatment of hormone-dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as Dual Aromatase-sulphatase Inhibitors (DASIs) emerged as an attractive approach for effective estrogen deprivation. The present review article focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hormone- related breast cancer.
Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Estrogens; Female; Humans; Sulfatases
PubMed: 33463462
DOI: 10.2174/1389557521666210119123840 -
International Journal of Molecular... May 2021Ovarian granulosa cells (GCs) are the most important source of estrogen. Therefore, aromatase (estrogen synthase), which is the key enzyme in estrogen synthesis, is not... (Review)
Review
Ovarian granulosa cells (GCs) are the most important source of estrogen. Therefore, aromatase (estrogen synthase), which is the key enzyme in estrogen synthesis, is not only an important factor of ovarian development, but also the key to estrogen secretion by GCs. Disorders of the ovarian estrogen secretion are more likely to induce female estrogen‑dependent diseases and fertility issues, such as ovarian cancer and polycystic ovary syndrome. Hence, aromatase is an important drug target; treatment with its inhibitors in estrogen‑dependent diseases has attracted increasing attention. The present review article focuses on the regulation and mechanism of the aromatase activity in the GCs, as well as the specific regulation of aromatase promoters. In GCs, follicle‑stimulating hormone (FSH) is dependent on the cyclic adenosine monophosphate (cAMP) pathway to regulate the aromatase activity, and the regulation of this enzyme is related to the activation of signaling pathways, such as phosphatidylinositol 3‑kinase (PI3K) and extracellular signal‑regulated kinase (ERK). In addition, endocrine‑disrupting substance and other related factors affect the expression of aromatase, which eventually create an imbalance in the estrogen secretion by the target tissues. The present review highlights these useful factors as potential inhibitors for target therapy.
Topics: Aromatase; Estrogens; Female; Granulosa Cells; Humans; Neoplasm Proteins; Ovarian Neoplasms; Polycystic Ovary Syndrome
PubMed: 33693952
DOI: 10.3892/ijmm.2021.4906 -
Medical Oncology (Northwood, London,... Dec 2022Coumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and... (Review)
Review
Coumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and the ease with which it may be transformed into a wide range of functionalized coumarins during synthesis, coumarin provides a privileged scaffold for medicinal chemists. As a result, many coumarin derivatives have been developed, synthesized, and evaluated to target a variety of therapeutic domains, thereby making it an attractive template for designing novel anti-breast cancer compounds. The main culprit in estrogen overproduction in the estrogen-dependent breast cancer (EDBC), is the enzyme aromatase (AR), and it is thought to be a significant target for the effective treatment of EDBC. Considering coumarins versatility, this review presents a detailed overview of diverse study of aromatase as a target for coumarins. An overview of structure-activity relationship analysis of coumarin core is also included so as to summarize the desired pharmacophoric features essential for design and development of aromatase inhibitors (AIs) using coumarin core. Identification of key synthesis techniques that could aid researchers in designing and developing novel analogues with significant anti-breast cancer properties along with their mechanism of action have also been covered in the current review.
Topics: Female; Humans; Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Chemistry, Pharmaceutical; Coumarins; Estrogens; Neoplasms, Hormone-Dependent
PubMed: 36471176
DOI: 10.1007/s12032-022-01916-4 -
European Journal of Histochemistry : EJH Aug 2023This study aimed at exploring the expression and clinical significance of aromatase P450, adhesion molecule CD24 and HER2/neu in endometrial cancer. The expression of...
This study aimed at exploring the expression and clinical significance of aromatase P450, adhesion molecule CD24 and HER2/neu in endometrial cancer. The expression of aromatase P450, adhesion molecule CD24 and HER2/neu was detected by immunohistochemistry in 15 cases of endometrial hyperplasia group, 50 cases of endometrial adenocarcinoma and 3 cases of uterine papillary adenocarcinoma, with 15 cases of normal endometrium as control group. We detected no expression of aromatase P450, adhesion molecule CD24 or HER2/neu in control group. Aromatase P450 positive expression rate was 66.7% in endometrial hyperplasia group and 70.3% in endometrial carcinoma group, without significant difference (p>0.05). There was no significant difference (p>0.05) in the positive expression rate of aromatase P450 between different myometrial invasion groups of endometrial adenocarcinomas. CD24 positive expression rate was 40.0% in endometrial hyperplasia group and 79.6% in endometrial carcinoma group, with significant difference (p<0.05). HER2/neu positive expression rate was 26.7% in the endometrial hyperplasia group and 57% in endometrial carcinoma group, with significant difference (p<0.05). In conclusion, aromatase P450 may be one factor associated with endometrial cancer cell proliferation, while CD24 and HER2/neu may be important factors associated with the invasion and metastasis of endometrial cancer.
Topics: Female; Humans; Endometrial Hyperplasia; Aromatase; Clinical Relevance; Endometrial Neoplasms; Immunohistochemistry; Endometrium; CD24 Antigen
PubMed: 37565251
DOI: 10.4081/ejh.2023.3655 -
Frontiers in Endocrinology 2020Traumatic brain injury (TBI) is responsible for various neuronal and cognitive deficits as well as psychosocial dysfunction. Characterized by damage inducing... (Review)
Review
Traumatic brain injury (TBI) is responsible for various neuronal and cognitive deficits as well as psychosocial dysfunction. Characterized by damage inducing neuroinflammation, this response can cause an acute secondary injury that leads to widespread neurodegeneration and loss of neurological function. Estrogens decrease injury induced neuroinflammation and increase cell survival and neuroprotection and thus are a potential target for use following TBI. While much is known about the role of estrogens as a neuroprotective agent following TBI, less is known regarding their formation and inactivation following damage to the brain. Specifically, very little is known surrounding the majority of enzymes responsible for the production of estrogens. These estrogen metabolizing enzymes (EME) include aromatase, steroid sulfatase (STS), estrogen sulfotransferase (EST/SULT1E1), and some forms of 17β-hydroxysteroid dehydrogenase (HSD17B) and are involved in both the initial conversion and interconversion of estrogens from precursors. This article will review and offer new prospective and ideas on the expression of EMEs following TBI.
Topics: Animals; Aromatase; Brain Injuries, Traumatic; Encephalitis; Estradiol Dehydrogenases; Estrogens; Humans; Neuroprotective Agents; Steryl-Sulfatase; Sulfotransferases
PubMed: 32547495
DOI: 10.3389/fendo.2020.00345 -
Anti-cancer Agents in Medicinal... 2022Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the...
BACKGROUND
Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation.
METHODS
The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells' capability to form colonies.
RESULT
Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC values after 48 hours of treatment with exemestane were 176, 180, and 120 μM in A549, H661, and H1299, respectively. Curcumin IC values after 48 hours were 80, 43, and 68 μM in A549, H661, and H1299, respectively. The combined treatment of exemestane or curcumin with cisplatin, raloxifene, and celecoxib resulted in a synergistic effect in the A549 lung cell line with a combination index of less than 1, suggesting synergism. Exemestane resulted in approximately 96% inhibition of wound closure at 100 μM, while curcumin resulted in approximately 63% inhibition of wound closure at 50 μM. Exemestane and curcumin inhibited the formation of cell colonies by reducing the number and size of formed colonies of A549, H661, and H1299 cell lines in a concentration dependent manner. Exemestane and curcumin had significantly induced apoptosis in A549 cells compared to control of untreated cells.
CONCLUSION
Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells.
Topics: Agar; Annexins; Apoptosis; Aromatase; Aromatase Inhibitors; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Humans; Lung Neoplasms; Propidium; Raloxifene Hydrochloride
PubMed: 35473535
DOI: 10.2174/1871520622666220426112435 -
Biomedicine & Pharmacotherapy =... Dec 2023Documented male-female differences in the risk of cardiovascular and chronic kidney diseases have been largely attributed to estrogens. The cardiovascular and renal... (Meta-Analysis)
Meta-Analysis Review
Documented male-female differences in the risk of cardiovascular and chronic kidney diseases have been largely attributed to estrogens. The cardiovascular and renal protective effects of estrogens are mediated via the activation of estrogen receptors (ERα and ERβ) and G protein-coupled estrogen receptor, and involve interactions with the renin-angiotensin-aldosterone system. Aromatase, also called estrogen synthase, is a cytochrome P-450 enzyme that plays a pivotal role in the conversion of androgens into estrogens. Estrogens are biosynthesized in gonadal and extra-gonadal sites by the action of aromatase. Evidence suggests that aromatase inhibitors, which are used to treat high estrogen-related pathologies, are associated with the development of cardiovascular events. We review the potential role of aromatization in providing cardio-renal protection and highlight several meta-analysis studies on cardiovascular events associated with aromatase inhibitors. Overall, we present the potential of aromatase enzyme as a fundamental contributor to cardio-renal protection.
Topics: Male; Female; Humans; Aromatase; Aromatase Inhibitors; Androgens; Estrogens; Receptors, Estrogen; Cardiovascular Diseases
PubMed: 37931519
DOI: 10.1016/j.biopha.2023.115832 -
Drug Design, Development and Therapy 2023Endometriosis is a chronic gynecologic condition that affects around 6-10% of reproductive age women. This clinical entity is characterized with pelvic pain,... (Review)
Review
Endometriosis is a chronic gynecologic condition that affects around 6-10% of reproductive age women. This clinical entity is characterized with pelvic pain, dysmenorrhea, dyspareunia, and infertility which are the most often presenting symptoms. Aromatase P450 is the key enzyme for ovarian estrogen biosynthesis and there is evidence that endometriotic lesions express aromatase and are able to synthesize their own estrogens. Aromatase inhibitors (AIs) are potent drugs that suppress the estrogen synthesis via suppression of aromatase. We performed a systematic review of systematic reviews and narrative reviews on the use of aromatase inhibitors in the medical management of endometriosis. We searched: PubMed (1950-2022), Google Scholar (2004-2022), Cochrane Library (2010-2022) and Researchgate (2010-2022). The search included the following medical subject headings (MeSH) or keywords: "Aromatase Inhibitors" AND "Endometriosis" AND "Systematic reviews" OR "Systematic review" AND "Reviews" OR "Reviews" AND "Endometriosis". The electronic database search yielded initially 12,106 studies from the different databases. Further assessment of the studies resulted in exclusion of (n = 12,015) studies due to duplicates and irrelevance; Finally, 24 studies were selected for inclusion, 5 were Systematic reviews and 19 were Narrative reviews. The 5 systematic reviews were assessed by AMSTAR-2 criteria and were found to have low quality. Narrative reviews were assessed with SANRA criteria and were found to have high-quality aromatase inhibitors are potent drugs that can manage the endometriosis-related symptoms in cases where initial medical management has failed to show positive results. However, their use is limited by the adverse effects that are linked with menopausal symptoms. aromatase inhibitors can be administered as an alternative treatment in patients. Future studies with randomized design are required to reach safer conclusions and further investigation. These studies should define the therapeutic dose, new add-back therapy modalities. Future directions should examine the most-appropriate way of administration and the duration of therapy.
Topics: Female; Humans; Aromatase; Aromatase Inhibitors; Endometriosis; Estrogens; Systematic Reviews as Topic
PubMed: 37168488
DOI: 10.2147/DDDT.S315726 -
Anti-cancer Agents in Medicinal... 2020Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences... (Review)
Review
BACKGROUND
Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences are reported in postmenopausal women and the concurrent risk surges with an increase in age. Since the enzyme aromatase catalyses essential steps in estrogen biosynthesis, Aromatase Inhibitors (AIs) are effective targeted therapy in patients with Estrogen Receptor positive (ER+) breast cancer. AIs are more effective than Selective Estrogen Receptor Modulators (SERMs) because they block both the genomic and nongenomic activities of ER. Till date, first, second and third-generation AIs have been approved by the FDA. The third-generation AIs, viz. Letrozole, Anastrozole, Exemestane, are currently used in the standard treatment for postmenopausal breast cancer.
METHODS
Data were collected from Medline, PubMed, Google Scholar, Science Direct through searching of keywords: 'aromatase', 'aromatase inhibitors', 'breast cancer', 'steroidal aromatase inhibitors', 'non-steroidal inhibitors' and 'generations of aromatase inhibitors'.
RESULTS
In the current scenario of breast cancer chemotherapy, AIs are the most widely used agents which reveal optimum efficacy along with the least side effects. Keeping in view the prominence of AIs in breast cancer therapy, this review covered the detailed description of aromatase including its role in the biosynthesis of estrogen, biochemistry, gene expression, 3D-structure, and information of reported AIs along with their role in breast cancer treatment.
CONCLUSION
AIs are the mainstream solution of the ER+ breast cancer treatment regimen with the continuous improvement of human understanding of the importance of a healthy life of women suffering from breast cancer.
Topics: Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Molecular Structure
PubMed: 32593281
DOI: 10.2174/1871520620666200627204105 -
Gene Nov 2022The genes coding for Cytochrome P450 aromatase (cyp19a1a and cyp19a1b) and estrogen (E) receptors (esr1, esr2a and esr2b) play a conserved role in ovarian...
The genes coding for Cytochrome P450 aromatase (cyp19a1a and cyp19a1b) and estrogen (E) receptors (esr1, esr2a and esr2b) play a conserved role in ovarian differentiation and development among teleosts. Classically, the "gonad form" of aromatase, coded by the cyp19a1a, is responsible for the ovarian differentiation in genetic females via ligation and activation of the Esr, which mediates the endocrine and exocrine signaling to allow or block the establishment of the feminine phenotype. However, in neotropical species, studies on the molecular and endocrine processes involved in gonad differentiation as well as on the effects of sex modulators are recent and scarce. In this study, we combined in silico analysis, real-time quantitative PCR (qPCR) assay and quantification of E plasma levels of differentiating tambaqui (Colossoma macropomum) to unveil the roles of the paralogs cypa19a1a and cyp19a1b during sex differentiation. Although the synteny of each gene is very conserved among characids, the genomic environment displays striking differences in comparison to model teleost species, with many rearrangements in cyp19a1a and cyp19a1b adjacencies and transposable element traces in both regulatory regions. The high dissimilarity (DI) of SF-1 binding motifs in cyp19a1a (DI = 10.06 to 14.90 %) and cyp19a1b (DI = 8.41 to 13.50 %) regulatory region, respectively, may reflect in an alternative pathway in tambaqui. Indeed, while low transcription of cyp19a1a was detected prior to sex differentiation, the expression of cyp19a1b and esr2a presented a large variation at this phase, which could be associated with sex-specific differential expression. Histological analysis revealed that anti-estradiol treatments did not affect gonadal sex ratios, although Fadrozole (50 mg kg of food) reduced E plasma levels (p < 0,005) as well cyp19a1a transcription; and tamoxifen (200 mg kg of food) down regulated both cyp19a1a and cyp19a1b but did not influence E levels. Altogether, our results bring into light new insights about the evolutionary fate of cyp19a1 paralogs in neotropical fish, which may have generated uncommon roles for the gonadal and brain forms of cyp19a1 genes and the unexpected lack of effect of endocrine disruptors on tambaqui sexual differentiation.
Topics: Animals; Aromatase; Characiformes; Female; Gonads; Male; Phylogeny; Sex Differentiation
PubMed: 35961435
DOI: 10.1016/j.gene.2022.146795