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This review presents the evolution of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer, describes late relapse phenomenon, provides clinical rationale for escalation of treatment, analyzes the key stages of the metastatic cascade, and provides a scientific rationale for the introduction of CDK4/6 inhibitors into adjuvant treatment regimens. The main results of two large randomized studies of therapy including abemaciclib (MonarchE) and ribociclib (NATALEE) in patients with early stages of hormone-dependent HER2-negative breast cancer are presented; the oncological results of escalation of treatment and the safety of therapy are assessed.

p-Coumaric acid is derived from cinnamic acid and is one of the major compounds in the Brazilian green propolis extract. Studies have shown that both p-coumaric acid and cinnamic acid have promising antiproliferative effects. In this context, aiming to increase the complexity of these active natural products and their activities, we performed coupling reactions with propargylamine and benzylamine, as well as with threonine, phenylalanine and lysine amino acids, aiming to enhance their antiproliferative effects towards the hormone-dependent breast cancer MCF-7 cells. Overall, the p-coumaric acid coupling with L-threonine amino acid (compound 15) had the best selectivity index (SI = 5.1), with half-maximal inhibitory concentration of 39.6 ± 1 µM, showing a high selectivity against hormone-dependent breast cancer cell lines MCF-7 and low cytotoxicity against the normal breast cell lines MCF-10A. Thus, this new natural product derivative may represent a prototype for the future development of antiproliferative agents, especially against hormone-dependent breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) ranks first in the morbidity pattern among women in Russia. Adjuvant endocrinotherapy is an important step in the complex treatment of premenopausal patients with hormone-positive early breast cancer. The drug ovarian suppression with GnRH-agonists have supplanted surgical castration and radiation-based treatment of the ovaries in patients with hormone-positive early breast cancer. Today, several drugs authorised for the treatment of breast cancer are used in clinical practice: goserelin, buserelin and triptorelin. Buserelin-depo is an effective method for achieving ovarian suppression. The results obtained do not differ from similar indicators obtained in using imported LHRH analogues.

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors. [ABSTRACT FROM AUTHOR]

The prevalence of breast cancer is steadily increasing with metastasis and thromboembolic complications identified as the most common causes of death. The acquisition of an aggressive phenotype by hormone-dependent breast cancers is mediated by Transforming Growth Factor Beta 1 (TGF-β1) expression and is associated with epithelial-mesenchymal transition (EMT) and, potentially, increased propensity for thrombosis. We investigated this phenomenon by assessing the effect of platelet-rich plasma (PRP) and whole blood (WB) on parameters of EMT and hypercoagulation in vitro. MCF-7 breast cancer cells were cultured under standard conditions, followed by co-culture with PRP or WB. Cells were processed for real-time PCR (TGF-β1 and vimentin), electron microscopy or immunocytochemistry (TGF-β1). Micrographs were qualitatively assessed, and real-time PCR data analyzed with PAST Statistical Software. The addition of blood components heightened TGF-β1 immunolocalization and significantly increased corresponding gene expression. Both PRP and WB significantly increased vimentin expression and induced a shape change from a typical epithelial phenotype to a spindle-shape morphology, indicative of EMT. Fibrin fiber, network and plaque formation indicated a hypercoagulatory environment. The results thus show that in preparation for hematogenous metastasis, hormone-dependent breast cancer cells assume an aggressive phenotype associated with EMT, simultaneously increasing the propensity for the formation of thrombo-emboli. [ABSTRACT FROM AUTHOR]

Introduction/Objective. Activation of insulin-like growth factor receptor (IGF-1R) results in cell transition from growth phase to synthesis phase of cell cycle. Breast cancer is categorized into prognostic and therapeutic subtypes based upon hormone receptor, estrogen receptor (ER), and progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (HER-2) expression. The objective of this study was to examine the expression of IGF-1R in а specific subtype invasive breast cancer and its correlation with basic histopathological and immunohistochemical prognostic parameters. Methods. Formalin-fixed paraffin-embedded tumor samples were obtained from 129 female patients with invasive breast cancer (I–III disease stage) with the follow-up ranging 36–108 months (average 48 months). For immunohistochemical staining, we used monoclonal antibodies for ER, PR, IGF-1R, and polyclonal antibody for HER-2. Results. IGF-1R inversely correlated with tumor stage (p = 0.017), tumor grade (p = 0.001), HER-2 (p = 0.003), whereas significant positive correlation was found with multifocality/multicentricity of breast cancer (p = 0.036), ER (p = 0.001) and PR (p = 0.0001) expression. Cox-regression analysis for relapse-free survival (RFS) showed that disease stage (p = 0.039) and HER-2 (p = 0.033) were independent prognostic factors. IGF-1R did not predict clinical outcome in patients with breast cancer (p = 0.488, Kaplan–Meier test for RFS). Conclusion. Patients with low stage and grade hormone-dependent breast cancer had a significantly higher IGF-1R expression than patients with triple negative or HER-2 overexpressed cancer. The present findings also highlight that IGF-1R expression in multicentric/multifocal breast cancer supports the key roles in tumor initiation.

Background. A clear relationship is now found between the activity of estrogen metabolites and the development of tumors in estrogen-dependent tissues. Many international and Russian studies could identify a number of compounds involved in the regulation of estrogen metabolites. Indole-3-carbinol is one of these compounds that correct a ratio of 2-hydroxyestrone (2-OHE1) to 16-OHE1. It is a phytonutrient that is contained in Cruciferous vegetables and has antitumor activity. Our investigations used highly purified indole-3-carbinol (Indinol). The ability to identify the role of metabolic syndrome, by applying the current methodological approaches, allowed us to study the effect of highly purified indole-3-carbinol on the level of expression of estrogen metabolites and to attempt to expand views on procedures to prevent and treat breast tumors. Materials and methods. A total of 136 women were comprehensively examined; of them 44 patients formed a group of those with morphologically verified hormone-independent breast cancer (BC) and 42 patients were a group of those with hormone-dependent BC. A control group included 50 women without signs of breast disease. In all the patients, body mass index was calculated; the ratio of urinary estrogen metabolites (2-ОНЕ1/16α-ОНЕ1) was quantified; and biopsy specimens and operative material were histologically and immunohistologically studied. Results. The BC patients were noted to have the high expression of 16α-OHE1 and the low values of 2-OHE1 (ratio, 0.42) as compared to the control group (2.09), which was an important component of metabolic syndrome. The BC patients had the high level of concomitant endocrine metabolic disturbances with the high body mass index, which reflected the clinical manifestation of metabolic syndrome. Indinol used to treat both hormone-dependent and hormone-independent BC showed an antimetabolic effect that was most pronounced 6 months later. Conclusion. Thus, early correction of metabolic disturbances with antimetabolites is one of the important, pathogenetically sound areas in the prevention of BC.

Background: The development of comorbidities has become increasingly relevant with longer-term cancer survival. Objective: To assess the pattern of comorbidities among Australian women with breast cancer treated with tamoxifen or an aromatase inhibitor. Design: Retrospective cohort study using Pharmaceutical Benefits Scheme (PBS) data (10% sample) from January 2003 to December 2014. Dispensing claims data were used to identify comorbidities and classified with the Rx-Risk-V model. The breast cancer cohort had tamoxifen or an aromatase inhibitor dispensed between 2004 and 2011 with no switching between types of endocrine therapy. Comparisons were made between the breast cancer cohort and specific control groups (age- and sex-matched at 1:10 ratio without any dispensing of anti-neoplastic agents during the study period) for the development of five individual comorbidities over time using Cox regression models. Results: Women treated with tamoxifen had a higher incidence of cardiovascular conditions, diabetes, and pain or pain-inflammation, but a lower incidence of hyperlipidaemia compared with non-cancer control groups, as indicated by PBS data. Women treated with aromatase inhibitors were more likely to develop cardiovascular conditions, osteoporosis, and pain or pain-inflammation compared with non-cancer control groups. The risks of hyperlipidaemia and osteoporosis were significantly lower among tamoxifen users compared with aromatase inhibitor users. Conclusion: Women with hormone-dependent breast cancer treated with an endocrine therapy had a higher risk of developing specified comorbid conditions than women without cancer, with different comorbidity profiles for those on tamoxifen versus aromatase inhibitors. Further research into the causes and mechanism of development and management of comorbidities after cancer is needed. [ABSTRACT FROM AUTHOR]

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERα (IC50 = 19 nM) and ERβ (IC50 = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC50 = 5.7 nM) and binding affinity to ERα (IC50 = 15 nM) and ERβ (IC50 = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers [ABSTRACT FROM AUTHOR]

p -Coumaric acid is derived from cinnamic acid and is one of the major compounds in the Brazilian green propolis extract. Studies have shown that both p -coumaric acid and cinnamic acid have promising antiproliferative effects. In this context, aiming to increase the complexity of these active natural products and their activities, we performed coupling reactions with propargylamine and benzylamine, as well as with threonine, phenylalanine and lysine amino acids, aiming to enhance their antiproliferative effects towards the hormone-dependent breast cancer MCF-7 cells. Overall, the p -coumaric acid coupling with L -threonine amino acid (compound 15 ) had the best selectivity index (SI = 5.1), with half-maximal inhibitory concentration of 39.6  ±  1 μM, showing a high selectivity against hormone-dependent breast cancer cell lines MCF-7 and low cytotoxicity against the normal breast cell lines MCF-10A. Thus, this new natural product derivative may represent a prototype for the future development of antiproliferative agents, especially against hormone-dependent breast cancer.

Aromatase inhibitors (AIs) are anti-tumor agents used in clinic to treat hormone-dependent breast cancer. AIs block estrogens biosynthesis by inhibiting the enzyme aromatase, preventing tumor progression. Exemestane, a third-generation steroidal AI, belongs to this class of drugs and is currently used in clinic to treat postmenopausal women, due to its high efficacy and good tolerability. Here, its pharmacological and biological aspects as well as its clinical applications and comparison to other endocrine therapeutic agents, are reviewed. It is also focused the benefits and risks of exemestane, drawbacks to be overcome and aspects to be explored. [ABSTRACT FROM AUTHOR]

In search of new anti-breast cancer agents, the present study envisaged the design and synthesis of a series of benzopyran-chalcones. All the synthesized compounds were assayed for their in-vitro anticancer activity against ER + MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines using SRB assay. The synthesized compounds were found active against ER + MCF-7 cell lines. Based on the in-vitro data, in-silico analysis was performed using hormone-dependent breast cancer targets such as hER-α and aromatase because the compounds showed activity against MCF-7 cells and none was active against MDA-MB-231. The in-silico results supported the in-vitro anticancer activity suggesting the affinity of compounds toward hormone-dependant breast cancer. Compounds 4A1 to 4A3 were found to be most cytotoxic to MCF-7 cells with IC 50 values of 31.87, 22.95, and 20.34 μg/ml, respectively (Doxorubicin IC 50 : <10 μg/ml). In addition, they showed the interactions with the amino acid residues of a binding cavity of an hER-α. Furthermore, quantitative structure-activity relationship (QSAR) studies were performed to reveal the vital structural features required for anticancer activity against breast cancer. Molecular dynamic simulation studies of hER-α and 4A3 in comparison with the raloxifene complex ensure the appropriate refinement of compounds in the dynamic system. Additionally, a generated pharmacophore model explored the essential pharmacophoric features of the synthesized scaffolds with respect to clinically used drug molecules for optimal hormone-dependant anti-breast cancer activity.Communicated by Ramaswamy H. Sarma.

Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC50 value: 0.9 nM) and ERβ (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy.

Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane undergoes a complex metabolization, giving rise to some already identified metabolites, the 17β-hydroxy-6-methylenandrosta-1,4-dien-3-one (17- βHE ) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione ( 6-HME ). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6β-spirooxiranandrosta-1,4-diene-3,17-dione ( 2 ), 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione ( 3 ) and 17-βHE ( 4 )) while one was acquired, the 6-HME ( 6 ). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure–activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-βHE ( 4 ) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC 50 0.25 μM vs 0.90 μM, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells. [ABSTRACT FROM AUTHOR]

Different hormonal therapies are used for estrogen receptor positive (ER) breast cancers, being the third-generation of aromatase inhibitors (AIs), an effective alternative to the classical tamoxifen. AIs inhibit the enzyme aromatase, which is responsible for catalyzing the conversion of androgens to estrogens. In this study, it was evaluated the effects of several steroidal AIs, namely 3β-hydroxyandrost-4-en-17-one ( 1), androst-4-en-17-one ( 12), 4α,5α-epoxyandrostan-17-one ( 13a) and 5α-androst-2-en-17-one ( 16), on cell proliferation, cell cycle progression and cell death in an ER aromatase-overexpressing human breast cancer cell line (MCF-7aro). All AIs induced a decrease in cell proliferation and these anti-proliferative effects were due to a disruption in cell cycle progression and cell death, by apoptosis. AIs 1 and 16 caused cell cycle arrest in G/G, while AIs 12 and 13a induced an arrest in G/M. Moreover, it was observed that these AIs induced apoptosis by different pathways, since AIs 1, 12 and 13a activated the apoptotic mitochondrial pathway, while AI 16 induced apoptosis through activation of caspase-8. These results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer cells and will also highlight the importance of AIs as inducers of apoptosis in hormone-dependent breast cancers. [ABSTRACT FROM AUTHOR]

The importance of the microenvironment in breast cancer growth and progression is becoming increasingly clear. Adipocytes are abundant in the mammary microenvironment, and recent studies show that adipocytes produce endocrine, inflammatory, and angiogenic factors that have tremendous potential to affect adjacent breast cancer cells. Yet, the extent to which local adipocyte function contributes to the pathogenesis of breast cancer is largely unexplored. Here we describe a unique animal model to study interactions between adipocytes and breast cancer cells in the tumor microenvironment. Our results suggest that local interactions between adipocytes and tumor cells are sufficient to promote the growth of hormone-dependent breast cancer. We also demonstrate that leptin signaling in adipocytes induces aromatase expression, expected to result in higher estrogen in the microenvironment thus enabling mammary tumorigenesis. [ABSTRACT FROM AUTHOR]

Abstract: Several therapeutic approaches are used in estrogen receptor positive (ER+) breast cancers, being one of them the use of aromatase inhibitors (AIs). Although AIs demonstrate higher efficacy than tamoxifen, they can also exhibit de novo or acquired resistance after prolonged treatment. Recently, we have described the synthesis and biochemical evaluation of four steroidal AIs, 3β-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4α,5α-epoxyandrostan-17-one (13a) and 5α-androst-2-en-17-one (16), obtained from modifications in the A-ring of the aromatase substrate, androstenedione. In this study, it was investigated the biological effects of these AIs in different breast cancer cell lines, an ER+ aromatase-overexpressing human breast cancer cell line (MCF-7aro cells), an estrogen-receptor negative (ER−) human breast cancer cell line (SK-BR-3 cells), and a late stage of acquired resistance cell line (LTEDaro cells). The effects of an autophagic inhibitor (3-methyladenine) plus AIs 1, 12, 13a or exemestane in LTEDaro cells were also studied to understand the involvement of autophagy in AI acquired resistance. Our results showed that these steroids inhibit aromatase of MCF-7aro cells and decrease cell viability in a dose- and time-dependent manner. The new AI 1 is the most potent inhibitor, although the AI 12 demonstrates to be the most effective in decreasing cell viability. Besides, and in advantage over exemestane, AIs 12 and 13a also reduced LTEDaro cells viability. The use of the autophagic inhibitor allowed AIs to diminish viability of LTEDaro cells, presenting a similar behavior to the sensitive cells. Thus, inhibition of autophagy may sensitize hormone-resistant cancer cells to anti-estrogen therapies. [Copyright &y& Elsevier]

Abstract: Hydrolysis of biologically inactive steroid sulfates to unconjugated steroids by steroid sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed. [Copyright &y& Elsevier]

Abstract: Human 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 is an enzyme that acts at the pre-receptor level. It catalyzes the NADPH-dependent reduction of the weak estrogen estrone into the most potent estrogen 17β-estradiol, which exerts proliferative effects via estrogen receptors. Overexpression of 17β-HSD type 1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis. 17β-HSD type 1 thus represents an attractive target for development of new drugs. Recently, we discovered that substituted coumarin derivatives potently and selectively inhibit 17β-HSD type 1. In the present study, we have performed additional biochemical and biological evaluation of the most promising coumarin derivative. First, we used an efficient method for isolation and purification of the active, soluble recombinant human 17β-HSD type 1 from Escherichia coli. This 17β-HSD type 1 showed a specific activity of 0.64±0.08μmolmin−1 mg−1 for estrone reduction in the presence of NADPH at pH 6.5, and a K m of 62nM for estrone. Next, we evaluated the best of the coumarin-derivative inhibitors, showing its reversible and competitive inhibition of 17β-HSD type 1 reductive activity with a K i of 53nM. We confirmed that this coumarin inhibitor acts not only in a cell-free assay, but also decreases endogenous 17β-HSD type 1 activity in human T-47D breast cancer cells. This inhibitor also reduced estrone dependent growth of T-47D cells after 48h of incubation. [Copyright &y& Elsevier]

Background: Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) acts at a pre-receptor level. It catalyzes NADPH-dependent reduction of the weak estrogen estrone into the most potent estrogen estradiol, which exerts its proliferative effects via estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis. 17β-HSD1 thus represents an attractive target for development of new drugs. Methods: We designed and synthesized a series of 3-, 5- and 6-phenyl indole derivatives as mimetics of the steroid substrate estrone. All of these compounds were evaluated for inhibition of recombinant human 17β-HSD1 from Escherichia coli, at concentrations of 0.6 μM and 6.0 μM. Results: Among 14 indole derivatives, compound 9 was an initial hit inhibitor of 17β-HSD1, with moderate inhibition (64% at 6 μM). Molecular docking into the crystal structure of 17β-HSD1 (1A27) revealed that this 5-phenyl indole derivative binds to 17β-HSD1 similarly to co-crystalized E2. Compound 9 forms two H-bonds with 17β-HSD1: one between the indole nitrogen and His222, and the second between the phenolic OH group and catalytic Tyr155. Conclusions: The indole scaffold is one of the possible starting points for the design of substrate mimetics of the steroid substrate estrone. Our study shows that these 6- and, especially, 5-phenol indole derivatives can act as moderate inhibitors of 17β-HSD1. Based on inhibition assays and docking simulations, we can infer further improvements of the 5-phenol indole derivatives that might result in better inhibition profiles. [ABSTRACT FROM AUTHOR]

Abstract: The estrogen receptor (ER) exists in two isoforms ERα and ERβ with a different distribution in the body and different functions which are not clearly identified yet. Thus, it is desirable to have both agonists and antagonists with selectivity for one or the other ER isoform available. In a previous study we showed that 2,5-diphenylfurans can be converted into pure antiestrogens with preference for ERα. When the arrangement of the phenyl rings was altered to a 2,4-substitution, the α-selectivity was lost as demonstrated by comparative assays using recombinant human ERα and ERβ. 3,5-Dialkyl-2,4-bis(4-hydroxyphenylfurans) were shown to act as agonists with preference for ERβ. Replacement of one of the alkyl groups by the [(pentylsulfanyl)propyl]aminohexyl side chain afforded estrogen antagonists without receptor selectivity. These derivatives were characterized as pure antiestrogens in transcription and proliferation assays in ER+ MCF-7 breast cancer cells. The most potent antagonists displayed IC50 values of ca. 20nM (fulvestrant 4nM). The data showed that the 2,4-arrangement of the phenyl rings in the furan structure increases the binding affinity for ERβ in comparison to the isomeric 2,5-diphenylfurans but does not lead to a pure antagonist with selectivity for ERβ. [Copyright &y& Elsevier]

Abstract: The estrogen receptor α (ERα) is understood to play an important role in the progression of breast cancer. Therefore, pure antiestrogens with a preference for this receptor form are of interest as new agents for the treatment of this malignancy. Several chemical structures with selective binding affinity for ERα have been identified and might be useful for the synthesis of ERα-selective pure antiestrogens. In this study we applied the 2,5-diphenylfuran system which is closely related to the triphenylfurans described by others. Various side chains with amino and/or sulfur functions were linked to C3 to convert the furans to estrogen antagonists without residual estrogenic activity. The degree of α-selectivity which ranges from 2.5- to 236-fold is strongly influenced by the alkyl group at C4. Antiestrogenic potency was determined in MCF-7/2a breast cancer cells stably transfected with a luciferase gene under the control of an ERE. The 2,5-bis(4-hydroxyphenyl)furan with an ethyl substituent and a 6-[N-methyl-N-(3-pentylthiopropyl)amino]hexyl side chain exerted the strongest antiestrogenic effect in this series with an IC50 value of 50nM in cells stimulated with 1nM estradiol. The RBA values of this derivative were 18% (ERα) and 3.4% (ERβ) of estradiol, respectively. It inhibited the growth of wild-type MCF-7 cells with an IC50 value of 22nM. The data show that the 2,5-diphenylfuran system is appropriate for the development of pure antiestrogens with preference for ERα. [Copyright &y& Elsevier]

In pursuit of novel steroid sulfatase (STS) inhibitors devoid of estrogenicity, several D-ring modified steroid derivatives were synthesised. In vitro evaluation of the compounds identified two highly potent inhibitors, 4a and 4b, which were 18 times more active than estrone-3-O-sulfamate (EMATE), both having IC50 values of ca. 1 nM. These 16,17-seco-estra-1,3,5(10)-triene-16,17-imide derivatives were synthesised from estrone, via the intermediate 1, which was easily alkylated, deprotected and sulfamoylated affording the final compounds in high yields. In order to assess their biological profile, the selected inhibitors were tested for their in vivo inhibitory potency and estrogenicity in ovariectomised rats. After an oral dose of 10 mg/kg per day for 5 days, 4a and 4b were found to inhibit rat liver steroid sulfatase by 99%. They were also devoid of estrogenic activity in the uterine weight gain assay, indicating that these two leads have therapeutic potential for the treatment of hormone-dependent breast cancer. [Copyright &y& Elsevier]

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)