Search Results (159)

Background/Objectives: Breast cancer was the leading cause of malignant tumors among women in 2022. About two-thirds of breast cancer cases are hormone-receptor-positive. In these patients, aromatase inhibitors are a mainstay of treatment, but associated musculoskeletal symptoms can negatively affect patient compliance. Aromatase-inhibitor-induced carpal tunnel syndrome represents one of the main causes of aromatase inhibitor discontinuation, with a non-compliance rate of up to 67%, potentially leading to increased cancer mortality. This study investigates estrogen receptor expression in aromatase-inhibitor-induced carpal tunnel syndrome tissues, in order to better define its etiopathogenesis and derive preventive or therapeutic measures that can improve aromatase inhibitor patient compliance. To our knowledge, there is no study on this subject in the literature. Methods: Between 2023 and 2024, we recruited 14 patients at the Jewish Hospital of Rome, including seven patients with aromatase-inhibitor-induced carpal tunnel syndrome (study group) and seven with postmenopausal idiopathic carpal tunnel syndrome (control group). Each patient was evaluated based on a clinical visit, a questionnaire, instrumental exams, and serum hormone dosages and were treated with open carpal tunnel release surgery, during which transverse carpal ligament and flexor tenosynovium samples were collected. For immunohistochemical experiments, sections were treated with anti-estrogen receptor α and anti-estrogen receptor β antibodies. Results: The immunohistochemical features in the study and control groups were similar, demonstrating that tissues affected by aromatase-inhibitor-induced carpal tunnel syndrome are targets of direct estrogen action and that estrogen deprivation is correlated with disease etiogenesis. Surgery was effective in patient treatment. Conclusions: Aromatase-inhibitor-induced carpal tunnel syndrome represents a newly defined form of the disease. This syndrome represents one of the main causes of aromatase inhibitor discontinuation, due to its negative impact on the patient’s quality of life. The identification by clinicians of aromatase inhibitor use as a possible risk factor for carpal tunnel syndrome development is of essential importance, as early diagnosis and prompt management can improve patient compliance and overall breast cancer treatment outcomes. Full article

Background: Standard treatment for patients with early-stage estrogen receptor-positive (ER+) breast cancer often includes sequential adjuvant radiation and endocrine therapies. Unfortunately, ~1/3 of patients eventually experience disease recurrence, partly due to residual disease in the form of drug-tolerant persister cancer cells. The anti-cancer efficacy of radiation therapy is partly attributable to the production of oxyradicals that damage biomolecules. We previously showed that endocrine therapy increases mitochondrial content in ER+ breast cancer cells; we postulated that this may also increase oxidative stress. Methods: Herein, we tested the efficacy of concurrent endocrine and radiation therapies, including both conventional (CDR) and ultra-high dose rate (UHDR) radiation. Results: We found that estrogen deprivation and radiation inhibit cell growth, induce apoptosis, and force cells into an oxidatively stressed state. DNA damage was almost exclusive to cells treated with the combination of endocrine and radiation therapy. Radiation slowed tumor growth in two xenograft models, and combination with estrogen deprivation prolonged the time to regrowth in ZR75-1 tumors. Conclusions: These findings indicate that simultaneous treatment with endocrine and radiation therapies can be advantageous, warranting further evaluation to identify tumor features predictive of response to individual and combination treatments. Full article

Background: Gestrinone is a synthetic hormone derived from 19-nortestosterone, exhibiting androgenic, anabolic, anti-progestogenic, and antiestrogenic effects. Gestrinone subcutaneous implants have been used “off label” for aesthetic purposes due to their anabolic action, promoting accelerated metabolism and muscle gain. Objective: Our goal is to conduct a systematic review focused exclusively on identifying the safety profile of gestrinone use, without addressing efficacy. Methods: This systematic review was performed according to the Joanna Briggs Institute and Cochrane Collaboration recommendations and is reported following the Preferred Reporting Items for Systematic Reviews and Network Meta-Analyses. This article’s searches were carried out in the PubMed, Embase, and Web of Science databases. Results: A total of 32 articles were included in this study. The reported adverse events associated with the use of gestrinone were amenorrhea (41.4% of cases), acne, seborrhea (42.7% of reports), decreased libido (26.5%), and hot flushes (24.2%). Other nonspecific symptoms such as hoarseness and cramps were also fairly reported (3.5% and 18.6%, respectively). Other reported effects were associated with breast size reduction (23.7% of patients) and increased transaminases (15.1%). Most studies (40%, n = 24 studies) found significant weight gain (ranging from 0.9 to 8 kg per patient). Abnormalities in bone mineral density were reported in four studies. Conclusions: The evidence remains insufficient to fully understand the risks of gestrinone uses associated with its widespread, unregulated use. Thus, further standardized studies and regulatory oversight to ensure patient safety are needed to mitigate potential health risks. Full article

The current study examined the in vitro antineoplastic potentials of centrapalus coumarin F (CCF) obtained from aerial parts of Centrapalus pauciflorus (Willd.) H.Rob. (Asteraceae). Cytotoxic activity was tested against a panel of human adherent cancer cell lines, including breast, cervical, and oropharyngeal cancer and glioblastoma. Cell cycle analyses using flow cytometry and Hoechst 33258-propidium iodide (HOPI) fluorescent double staining were used to describe the proapoptotic property of CCF. Wound healing assessment and the Boyden chamber assay were performed to characterize the antimetastatic action of the compound. The firefly luciferase assay was applied to clarify the action of CCF on estrogenic receptors. CCF demonstrated remarkable selective growth inhibition against the HPV-18-positive human cervical cancer cell line HeLa (IC₅₀ = 2.28 µM). The compound elicited crucial markers of apoptosis, inhibited the migration and invasion capacity of HeLa cells, and demonstrated an antiestrogenic property. Our current data indicate that the meroterpenoid scaffold presented here displays remarkable antiproliferative and antimetastatic effects on HeLa cells and can be considered a valuable model for designing further analogs targeting cervical carcinoma. Full article

Breast Cancer Gene 1 (BRCA1) offers a potential approach for ERα repression by blocking cyclin D1’s interaction with ERα, which prevents cells from growing and dividing too rapidly or uncontrollably. When BRCA1 levels are low, BRCA1 mimetics fit into the BRCA1-binding pocket within ERα, mimicking the ability of BRCA1 to inhibit ERα activity. This study aims to identify a novel class of lead molecules for BRCA1 mimetics for ER-positive breast cancer, distinct from conventional antiestrogen therapies in their mechanism of action. In this article, coumarin thiosemicarbazone hybrids were synthesized from 7-hydroxy 4-methyl coumarin/4-hydroxy coumarin and thiosemicarbazide with different aldehydes and evaluated for their ERα repression activity. The most active compounds in the series, 9b, 9l, and 9m, exhibited significant potency with an IC₅₀ value of 14.49 µM, 35.08 µM and 42.12 µM, respectively, compared to raloxifene (reported) as the positive control with an IC₅₀ value of 13.7 µM. The gene expression study confirmed the downregulation of the cyclin D1 gene for the compounds 9l (−0.217) and 9m (−0.214). Similarly, the downregulation of the BCL2 gene for the compounds 9b (−0.373), 9l (−0.320), and 9m (−0.376). Also, molecular docking studies and MMGBSA were performed to determine key interactions between compounds and ERα at the BRCA1 binding pocket (AA 338–387). In silico, ADMET properties were executed to illustrate the druggability and safety of the novel derivatives. In silico, in vitro, and gene expression studies revealed that among all the compounds, 9b, 9l, and 9m are promising candidates for the development of lead molecules targeting ERα inhibitors for breast cancer treatment. Moreover, the concept of ERα repression with small molecules as BRCA1 mimetics is novel. In general, it can be concluded that these compounds can serve as promising leads to the design of potential BRCA1 mimetics. Full article

Cancer remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for novel therapeutic agents. This study investigated the synthesis and biological evaluation of O-alkyl (E)-chalcone derivatives (4a–4v) as potential anticancer agents. The compounds were synthesized via aldol condensation of substituted aldehydes and acetophenones, with structures confirmed by IR, NMR, and mass spectrometry. In vitro cytotoxicity assays revealed varying effectiveness, with compounds 4a, 4b, 4q, and 4v exhibiting potent activity against MDA-MB-231 and MCF-7, showing IC₅₀ values between 2.08 and 13.58 µM, besides HCT-116 and HeLa cancer cell lines (IC₅₀ values between 6.59 and 22.64 µM). Notably, compound 4b displayed remarkable selectivity, with an IC₅₀ of 54.59 µM against the non-cancerous WI-38 cell line. Additionally, protein kinase inhibition assays indicated that compounds 4b and 4q effectively inhibited EGFR and VEGFR-2, with 4b outperforming the standard inhibitor erlotinib. Molecular docking studies of compound 4q showed strong binding affinities in the ATP-binding pockets of EGFR, HER2, VEGFR2, and CDK2. In silico analyses further highlighted the favorable pharmacokinetic properties of compound 4q, underscoring its potential as a selective tyrosine kinase inhibitor. These findings suggest the therapeutic promise of O-alkyl (E)-chalcone derivatives in cancer treatment. Full article

Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer—the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer. Full article

Background/Objectives: Estrogen receptor-α coactivator MED1 is overexpressed in 40–60% of human breast cancers, and its high expression correlates with poor disease-free survival of patients undergoing anti-estrogen therapy. However, the molecular mechanism underlying MED1 upregulation and activation in breast cancer treatment resistance remains elusive. Methods: miRNA and mRNA expression analysis was performed using the NCBI GEO database. MED1 targeting and its impact on therapy resistance was evaluated in control and tamoxifen-resistant breast cancer cell lines by miR-205 overexpression and inhibition. Immunoblotting, chromatin immunoprecipitation, and luciferase reporter assays were used to understand the molecular mechanism of MED1-mediated tamoxifen resistance. Mice xenograft models were used to validate treatment efficacy and molecular mechanisms in vivo. Results: miR-205 was found to directly target and suppress the expression of MED1 through bioinformatic analyses and experimental validations. An inverse correlation of miR-205 and MED1 was observed in breast cancer patients with high MED1/low miR-205, indicative of poor prognosis in long-term anti-estrogen treatment. Furthermore, the depletion of miR-205 was observed in tamoxifen-resistant breast cancer cells overexpressing MED1. The restoration of miR-205 expression attenuated MED1 expression and re-sensitized cells to tamoxifen both in vitro and in vivo. Interestingly, miR205 was also found to target another key regulatory gene, HER3, which drives PI3K/Akt signaling and MED1 activation by phosphorylation. Importantly, we found ER target gene transcription and promoter cofactor recruitment by tamoxifen can be reversed by induced miR205 expression. Conclusions: Altogether, miR-205 functions as a negative regulator of MED1 and HER3, affecting the regulation of the HER3-PI3K/Akt-MED1 axis in anti-estrogen resistance, and could serve as a potential therapeutic regime to overcome treatment resistance. Full article

Background/Objectives: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited. Gedatolisib, a well-tolerated panPI3K/mTOR inhibitor targeting all Class I PI3K isoforms, mTORC1 and mTORC2, could represent an effective treatment option for patients with gynecologic cancers. Methods: Gedatolisib and other PAM inhibitors (e.g., alpelisib, capivasertib, and everolimus) were tested in endometrial, ovarian, and cervical cancer cell lines by using cell viability, cell proliferation, and flow cytometry assays. Xenograft studies evaluated gedatolisib in combination with a CDK4/6 inhibitor (palbociclib) or an anti-estrogen (fulvestrant). A pseudo-temporal transcriptomic trajectory of endometrial cancer clinical progression was computationally modeled employing data from 554 patients to correlate non-clinical studies with a potential patient group. Results: Gedatolisib induced a substantial decrease in PAM pathway activity in association with the inhibition of cell cycle progression and the decreased cell viability in vitro. Compared to single-node PAM inhibitors, gedatolisib exhibited greater growth-inhibitory effects in almost all cell lines, regardless of the PAM pathway mutations. Gedatolisib combined with either fulvestrant or palbociclib inhibited tumor growth in endometrial and ovarian cancer xenograft models. Conclusions: Gedatolisib in combination with other therapies has shown an acceptable safety profile and promising preliminary efficacy in clinical studies with various solid tumor types. The non-clinical data presented here support the development of gedatolisib combined with CDK4/6 inhibitors and/or hormonal therapy for gynecologic cancer treatment. Full article

Background: Estrogen receptor-positive breast cancer accounts for around 70% of all cases. Tamoxifen, an anti-estrogenic inhibitor, is the primary drug used for this type of breast cancer treatment. However, tamoxifen resistance is a major challenge in clinics. Metabolic reprogramming, an emerging hallmark of cancer, plays a key role in cancer initiation, progression, and therapy resistance. The metabolism of non-essential amino acids such as serine, proline, and glutamine is involved in tumor metabolism reprogramming. Although the association of glutamine metabolism with tamoxifen resistance has been well established, the role of proline metabolism and its critical enzyme PRODH is unknown. Objective: The aim of this study is to explore the role and mechanism of PRODH in tamoxifen resistance in breast cancer cells. Methods: PRODH and GPX4 expressions in tamoxifen-resistant cells were detected using real-time PCR and Western blot analysis. The breast cells’ response to tamoxifen was measured using MTT assays. Trans-well assays were used to detect cell migration and invasion. A Xenograft tumor assay was used to detect the role of PRODH in tumor growth. Reactive oxygen species were measured using flow cytometry. Results: PRODH expression is reduced in tamoxifen-resistant cells, and its overexpression enhances tamoxifen response in vitro and in vivo. Conversely, PRODH knockdown confers tamoxifen resistance in tamoxifen-sensitive cells. Mechanistic studies show that ferroptosis is inhibited in tamoxifen-resistant cells and overexpression of PRODH restores the ferroptosis in tamoxifen-resistant cells. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the effect of PRODH on tamoxifen resistance. Conclusions: These findings suggest that PRODH regulates tamoxifen resistance by regulating ferroptosis in tamoxifen-resistant cells. Full article

Considering the properties of myo-inositol (MI) and D-chiro-inositol (DCI), which are well known in polycystic ovary syndrome therapy, and the limitations of adult granulosa cell tumor (AGCT) treatment, especially for androgen-secreting tumors, we studied the role of MI and DCI in the androgen-rich environment of AGCTs. For this purpose, we analyzed the mRNA expression of steroidogenic genes and the secretion of progesterone (P4) and 17β-estradiol (E2) in an unstimulated and/or dihydrotestosterone (DHT)-stimulated environment under MI and DCI influence. Thus, we used the HGrC1 and KGN cell lines as in vitro models of healthy and cancerous granulosa cells. We found that DHT, the most potent androgen, increased E2 secretion and steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage gene (CYP11A1) mRNA expression without affecting 450 aromatase (CYP19A1) in AGCTs. However, after the MI and DCI treatment of KGN cells, both compounds strongly reduced StAR and CYP11A1 expression. Interestingly, in DHT-stimulated KGN cells, only DCI alone and its cotreatment with MI reduced both CYP11A1 mRNA and E2 secretion. These findings suggest that CYP11A1 is responsible for the antiestrogenic effect of DCI in the androgen-rich environment of AGCTs. Therefore, MI and DCI could be used as effective agents in the adjuvant treatment of AGCT, but further detailed studies are needed. Full article

Background: Breast cancer incidence and mortality exhibit a rising trend globally among both premenopausal and postmenopausal women, suggesting that there are serious errors in our preventive and therapeutic measures. Purpose: Providing a series of valuable, but misunderstood inventions highlighting the role of increasing estrogen signaling in prevention and therapy of breast cancer instead of its inhibition. Results: 1. Breast cells and breast cancer cells with germline BRCA1/2 mutations similarly show defects in liganded estrogen receptor (ER) signaling, demonstrating its role in genomic instability and cancer initiation. 2. In breast tumors, the increased expression of special receptor family maybe an effort for self-directed improvement of genomic defects, while the weakness or loss of receptors indicates a defect requiring medical repair. 3. ER overexpression in breast cancer cells is capable of strengthening estrogen signaling and DNA repair, while in ER negative tumors, HER2 overexpression tries to upregulate unliganded ER activation and genome stabilization. 4. ER-positive breast cancers responsive to endocrine therapy may show a compensatory ER overexpression resulting in a transient tumor response. Breast cancers non-responsive to antiestrogen treatment exhibit HER2-overexpression for compensating the complete inhibition of hormonal ER activation. 5. In breast tumors, somatic mutations serve upregulation of ER activation via liganded or unliganded pathway helping genome stabilization and apoptotic death. 6. The mutual communication between breast cancer and its inflammatory environment is a wonderful partnership among cells fighting for genome stabilization and apoptotic death of tumor. 7. In breast cancers, there is no resistance to genotoxic or immune blocker therapies, but rather, the nonresponsive tumor cells exhaust all compensatory possibilities against therapeutic damages. Conclusions: Understanding the behavior and ambition of breast cancer cells may achieve a turn in therapy via applying supportive care instead of genotoxic measures. Full article

This work examined the potential benefit of curcumin in breast cancer patients as a supplementary drug in ER-positive cancers. The results indicated that in the MCF-7 human breast cancer cell line, E2 and curcumin decreased cell proliferation and the colony-forming capacity and down-regulated protein expression as well as important molecules associated with cell proliferation, such as PCNA and estrogen receptor alpha; genes associated with the epithelial-mesenchymal transition, such as β-catenin, Vimentin, and E-cadherin; and molecules associated with apoptosis. Clinical studies in bioinformatics have indicated a positive correlation between ESR1 and either CCND1 or BCL2 gene expression in all breast cancer patients. Thus, curcumin could become a potential natural adjuvant treatment for patients with estrogen receptor alpha-positive breast cancer and those with resistance or a poor response to endocrine therapy since the reactivation of estrogen receptor alpha is inevitable. Full article

Anti-estrogenic therapy is established in the management of estrogen receptor (ER)-positive breast cancer. However, to overcome resistance and improve therapeutic outcome, novel strategies are needed such as targeting widely recognized aberrant epigenetics. The study aims to investigate the combination of the aromatase inhibitor exemestane and the histone deacetylase (HDAC) inhibitor and antioxidant α-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of α-lipoic acid, and rac-dihydro-lipoic acid were investigated for HDAC inhibition. We found HDAC inhibitory activity in the 1–3-digit micromolar range with a preference for HDAC6. Rac-dihydro-lipoic acid is slightly more potent than rac-α-lipoic acid. The antiproliferative IC₅₀ value of α-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and α-lipoic acid resulted in synergistic behavior under various incubation times (24 h to 10 d) and readouts (MTT, live-cell fluorescence microscopy, caspase activation) analyzed by the Chou–Talalay method. α-lipoic acid increases mitochondrial fusion and the expression of apoptosis-related proteins p21, APAF-1, BIM, FOXO1, and decreases expression of anti-apoptotic proteins survivin, BCL-2, and c-myc. In conclusion, combining exemestane with α-lipoic acid is a promising novel treatment option for ER-positive breast cancer. Full article

Manuka honey (MH) exhibits potential antitumor activity in preclinical models of a number of human cancers. Treatment in vitro with MH at concentrations ranging from 0.3 to 5.0% (w/v) led to significant dose-dependent inhibition of proliferation of human breast cancer MCF-7 cells, but anti-proliferative effects of MH were less pronounced in MDA-MB-231 breast cancer cells. Effects of MH were also tested on non-malignant human mammary epithelial cells (HMECs) at 2.5% w/v, and it was found that MH reduced the proliferation of MCF-7 cells but not that of HMECs. Notably, the antitumor activity of MH was in the range of that exerted by treatment of MCF-7 cells with the antiestrogen tamoxifen. Further, MH treatment stimulated apoptosis of MCF-7 cells in vitro, with most cells exhibiting acute and significant levels of apoptosis that correlated with PARP activation. Additionally, the effects of MH induced the activation of AMPK and inhibition of AKT/mTOR downstream signaling. Treatment of MCF7 cells with increased concentrations of MH induced AMPK phosphorylation in a dose-dependent manner that was accompanied by inhibition of phosphorylation of AKT and mTOR downstream effector protein S6. In addition, MH reduced phosphorylated STAT3 levels in vitro, which may correlate with MH and AMPK-mediated anti-inflammatory properties. Further, in vivo, MH administered alone significantly inhibited the growth of established MCF-7 tumors in nude mice by 84%, resulting in an observable reduction in tumor volume. Our findings highlight the need for further research into the use of natural compounds, such as MH, for antitumor efficacy and potential chemoprevention and investigation of molecular pathways underlying these actions. Full article