Standard Tamoxifen Research Articles

Synthesis, and In-silico Studies of Indole-chalcone Derivatives Targeting Estrogen Receptor Alpha (ER-α) for Breast Cancer.

Breast cancer is the prominent reason of death in women worldwide, and the cases are increasing day by day. There are many FDA-approved drugs for treating breast cancer. Due to drug resistance, and problems in selectivity, there is a need to develop more effective agents with few side effects. Indole derivatives have demonstrated significant pharmacological potential as anti-breast cancer agents. Further, chalcone derivatives incorporating heterocyclic scaffolds play a significant role in medicine. Indole-chalcone-based compounds offer the potential for improved biological activity and enhanced drug-like properties. It prompted us to explore the synthesis of Indole-Chalcone derivatives targeting estrogen receptor alpha (ER-α) to discover potent anti-breast cancer agents. To synthesize indole-chalcone derivatives and study their binding interactions for ER-α protein by molecular docking for breast cancer treatment. In this study, indole-chalcone derivatives have been synthesized using conventional heating. With the help of Schrodinger software, molecular interaction as well as ADME (Adsorption, Distribution, Metabolism, and Excretion) studies of the compounds were conducted. Among all the synthesized compounds, four compounds (1, 2, 3, and 4) showed better docking scores (-10.24 kcal/mol, -10.15 kcal/mol, -9.40 kcal/mol, -9.29 kcal/mol, respectively) than the standard tamoxifen (-8.43 kcal/mol). From In-silico studies, we can conclude that four compounds from the synthesized series fit into the active site of ER-α. ADME properties of synthesized derivatives were found in the acceptable range. In the future, these compounds can be further explored for biological activity.

Identification of Novel Inhibitors for ERα Target of Breast Cancer By In Silico Approach

Background: Estrogen alpha has been recognized as a perilous factor in breast cancer cell proliferation and has been proficiently treated in breast cancer chemotherapy with the development of selective estrogen receptor modulators (SERMs). Objectives: The major aim of this study was to identify the potential inhibitors against the most influential target ERα receptor by in silico studies of 115 phytochemicals from 17 medicinal plants using in silico molecular docking studies. Methods: The molecular docking investigation was carried out by a genetic algorithm using the Auto Dock Vina program, and the validation of docking was also performed using molecular dynamic (MD) simulation by the Desmond tool of Schrödinger molecular modeling. The ADME( T) studies were performed by SWISS ADME and ProTox-II. Results: The top ten highest binding energy phytochemicals identified were amyrin acetate (- 10.7 kcal/mol), uscharine (-10.5 kcal/mol), voruscharin (-10.0 kcal/mol), cyclitols (-10.0 kcal/mol), taraxeryl acetate (-9.9 kcal/mol), amyrin (-9.9 kcal/mol), barringtogenol C (-9.9 kcal/mol), calactin (-9.9 kcal/mol), 3-beta taraxerol (-9.8 kcal/mol), and calotoxin (-9.8 kcal/mol). A molecular docking study revealed that these phytochemical constituents showed higher binding affinity compared to the reference standard tamoxifen (-6.6 kcal/mol) towards the target protein ERα. The results of MD studies showed that all four tested compounds possess comparatively stable ligand-protein complexes with ERα target as compared to the tamoxifen- ERα complex. Conclusion: Among the ten compounds, phytochemical amyrin acetate (triterpenoids) formed a more stable complex as well as exhibited greater binding affinity than standard tamoxifen. ADMET studies for the top ten phytochemicals showed a good safety profile. Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for the treatment of breast cancer by adopting the concept of drug repurposing. Hence, these phytochemicals can be further studied and can be used as a parent core molecule to develop novel lead molecules for breast cancer therapy.

Computational Screening of Some Phytochemicals to Identify Best Modulators for Ligand Binding Domain of Estrogen Receptor Alpha.

The peculiar aim of this study is to discover and identify the most effective and potential inhibitors against the most influential target ERα receptor by in silico studies of 45 phytochemicals from six diverse ayurvedic medicinal plants. The molecular docking investigation was carried out by the genetic algorithm program of AutoDock Vina. The molecular dynamic (MD) simulation investigations were conducted using the Desmond tool of Schrödinger molecular modelling. This study identified the top ten highest binding energy phytochemicals that were taken for drug-likeness test and ADMET profile prediction with the help of the web-based server QikpropADME. Molecular docking study revealed that ellagic acid (-9.3 kcal/mol), emodin (-9.1 kcal/mol), rhein (-9.1 kcal/mol), andquercetin (-9.0 kcal/mol) phytochemicals showed similar binding affinity as standard tamoxifen towards the target protein ERα. MD studies showed that all four compounds possess comparatively stable ligand-protein complexes with ERα target compared to the tamoxifen-ERα complex. Among the four compounds, phytochemical rhein formed a more stable complex than standard tamoxifen. ADMET studies for the top ten highest binding energy phytochemicals showed a better safety profile. Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for treating breast cancer, according to the notion of drug repurposing. Hence, these phytochemicals can be further studied and used as a parent core molecule to develop innovative lead molecules for breast cancer therapy.

Cytotoxic Evaluation, Molecular Docking, and 2D-QSAR Studies of Dihydropyrimidinone Derivatives as Potential Anticancer Agents.

The diverse pharmacological role of dihydropyrimidinone scaffold has made it to be an interesting drug target. Because of the high incidence and mortality rate of breast cancer, there is a dire need of discovering new pharmacotherapeutic agents in managing this disease. A series of twenty-two derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a-3k) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-4k) synthesized in a previous study were evaluated for their anticancer potential against breast cancer cell line. Molecular docking studies were performed to analyze the binding mode and interaction pattern of these compounds against nine breast cancer target proteins. The in vitro cell proliferation assay was performed against the breast cancer cell line MCF-7. The structure activity relationship of these compounds was further studied using QSARINS. Among nine proteins, the docking analysis revealed efficient binding of compounds 4f, 4e, 3e, 4g, and 4h against all target proteins. The in vitro cytotoxic assay revealed significant anticancer activity of compound 4f having IC50 of 2.15 μM. The compounds 4e, 3e, 4g, and 4h also showed anticancer activities with IC50 of 2.401, 2.41, 2.47 and 2.33 μM, respectively. The standard tamoxifen showed IC50 1.88 μM. The 2D qualitative structure-activity relationship (QSAR) analysis was also carried out to identify potential breast cancer targets through QSARINS. The final QSAR equation revealed good predictivity and statistical validation R2 and Q2 values for the model obtained from QSARINS was 0.98 and 0.97, respectively. The active compounds showed very good anticancer activities, and the binding analysis has revealed stable hydrogen bonding of these compounds with the target proteins. Moreover, the QSAR analysis has predicted useful information on the structural requirement of these compounds as anticancer agents with the importance of topological and autocorrelated descriptors in effecting the cancer activities.

In-silico DESIGN SCREENING OF SOME PYRAZOLONE FUSED HETEROCYCLIC ANALOGUES AS HER2 INHIBITORS TARGETING BREAST CANCER

In human breast cancers, the human epidermal development factor receptor-2 is a membrane tyrosine kinase that is overexpressed, and gene amplified. Pyrazolone fused heterocyclic moieties- thiazolidinone, carboxymethyl thiazolidinone, azetidinone are significant DNA-intercalating agents here human epidermal development factor receptor-2 amplification and over expression are linked to tumour cell proliferation and the pathway of instances in breast cancer. Few novel pyrazolone fused heterocyclic analogues are designed by in-silico-technique for their human epidermal development factor receptor-2 inhibition action. Docking patterns of compounds 4A1-4A10 are carried out against human epidermal development factor receptor-2 (PDB id-3RCD) by using Schrodinger suite 2016-2. Molecular docking study for the framed moieties 4A1-4A10 were performed by Glide XP module of Schrodinger suite. The affinity of binding as chosen based on the Glide score. Many compounds were showing good hydrophobic and hydrogen bonding communication and association in order to hinder human epidermal development factor receptor-2. The derivatives 4A1-4A10 have significant glide scores in the scope of -4.476 to - 6.234 compared with the standard Tamoxifen (-7.893). The in-silico screening properties are within the druglikeness. The results proved that this study gave a shred of evidence for the consideration of Pyrazolone fused heterocyclic analogues as potential human epidermal development factor receptor-2 inhibitors. Among the compounds, 4A1-4A10 with significant glide scores may produce significant anti-breast cancer activity and further in-vitro and in-vivo investigations may prove their therapeutic potential. The precursor phenyl hydrazine is reacted with ethylacetoacetate to give 5-methyl-2-phenyl-2,-dihydro-3H-pyrazol-one derivatives. Also, the reactivity of the precursor towards Schiff base derivatives of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-one to give the hetero analogues of thiazolidinone derivatives was studied.

Insilico design, ADMET screening, MM-GBSA binding free energy of novel 1,3,4 oxadiazoles linked Schiff bases as PARP-1 inhibitors targeting breast cancer

BackgroundPoly(ADP-ribose) polymerases (PARPs), a nuclear protein belongs to a new class of drugs, which mainly target tumours with DNA repair defects. They are mainly involved in the multiple cellular processes in addition to the DNA repair process. They act directly on the base excision repair, which is considered as one of the important pathway for cell survival in breast cancer. These belong to the active members of DNA repair assembly and evolved as a key target in the anti-cancer drug discovery. 1,3,4-Oxadiazoles are also well known anticancer agents.ResultsA novel series of 1,3,4-oxadiazoles linked to Schiff bases (T1-21) were designed and subjected to In-silico analysis against PARP-1 (PDB ID:5DS3) enzyme targeting against breast cancer. Molecular docking study for the designed compounds (T1-21) was performed by In-silico ADMET screening by QikProp module, Glide module and MM-GBSA binding free energy calculations by using Schrodinger suit 2019–2. The PARP-1 enzyme shows the binding affinity against the newly designed molecules (T1-21) based on the glide scores. Compounds T21, T12 showed very good glide score by the molecular docking studies and compared with the standard Tamoxifen. The binding free energies by the MM-GBSA assay were found to be consistent. The pharmacokinetic (ADMET) parameters of all the newly designed compounds were found to be in the acceptable range.ConclusionThe selected 1,3,4-oxadiazole-schiff base conjugates seems to be one of the potential source for the further development of anticancer agents against PARP-1 enzyme. The results revealed that some of the compounds T21, T17, T14, T13, T12, T8 with good glide scores showed very significant activity against breast cancer

Abstract PS7-30: Differential efficacy, safety and tolerability of low-dose versus standard dose tamoxifen as breast cancer prophylaxis: A network meta-analysis

Abstract BACKGROUND: Despite reduction in the risk of breast cancer occurrence, the use of prophylactic tamoxifen does not improve longer term outcomes such as survival and comes at the cost of toxicity. As such, chemoprophylaxis is utilized poorly in routine practice. Lower dose tamoxifen has been proposed as a more acceptable alternative for breast cancer prevention. Here, we explore efficacy and treatment-related adverse events (TRAEs) comparing the two tamoxifen dosing regimens in a network meta-analysis. METHOD: We searched PubMed to identify randomized trials (RCTs) of tamoxifen for breast cancer prophylaxis in high-risk patients (as defined in individual trials). Low-dose tamoxifen was defined as less than 20mg per day. We extracted the hazard ratio (HR) for breast cancer events relative to placebo. We also collected data on common and serious TRAE, and calculated odd ratios (OR) for each TRAE relative to placebo. Data were then included in a network meta-analysis comparing low-dose (experimental group) to standard dose tamoxifen (control group). Associations between TRAEs and patient charactericstics were explored using meta-regression which comprised a weighted linear regression using mixed effects modelling. RESULTS: Ten RCTs comprising 35,505 patients were included in the analysis (4 low-dose trials (n=3712 patients) and 6 standard dose trials (n=31,793 patients). There were no significant differences between low-dose and standard dose trials in age (53.3 vs 50.8, p=0.25), post-menopausal status (77.5% vs 49%, p=0.63) or BMI (24.1kg/m2 vs 26.95 kg/m2, p=0.40). Efficacy was similar between the two dosage regimens (HR for breast cancer recurrences: 1.04, 95% CI 0.77-1.41, p=0.78 and for invasive breast cancer: 1.04, 95% CI 0.69-1.56, p=0.85). Differences in TRAEs are shown in the Table. There was a statistically significant reduction in headache with low-dose tamoxifen, and a non-significant reduction in endometrial cancers, other cancers, cardiovascular diseases and all-cause deaths. Hot flashes, vaginal bleeding and endometrial polyps were non-significantly higher with low-dose tamoxifen. In meta-regression analysis, age was associated with lower risk of endometrial carcinoma (p=0.049) and hot flashes (p=0.03). CONCLUSION: The use of prophylactic low-dose tamoxifen provides similar efficacy to standard dosing, but may reduce the risk of certain common and serious TRAEs. TRAEOR95% CIp-valueDeaths0.630.14-2.860.55Endometrial cancer0.320.08-1.240.10Endometrial polyps1.660.84-3.280.15Other cancer0.710.40-1.260.24DVT or PE0.900.12-7.580.93 Coronary heart disease0.720.24-2.150.56Cerebrovascular disease1.600.29-8.970.59Hot flashes1.340.63-2.860.45Vaginal dryness0.840.34-2.030.69Vaginal bleeding1.260.52-3.060.61Vaginal discharge1.080.58-1.990.81Headache0.110.05-0.860.04 Citation Format: Alexandra Desnoyers, Michelle B Nadler, Brooke E Wilson, Eitan Amir. Differential efficacy, safety and tolerability of low-dose versus standard dose tamoxifen as breast cancer prophylaxis: A network meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-30.

Antioxidant, Thrombolytic, Antimicrobial and Cytotoxic Activities of Flavonoids Isolated from the Root Bark of Pongamia pinnata

The crude methanolic extract of the root bark of Pongamia pinnata was taken into consideration to isolate secondary metabolites. A total six known natural compounds were separated and purified by various chromatographic techniques and five isolates were identified as flavonoid derivatives such as pongachromene (1), kanugin (2), karanjin (3), demethoxykanugin (4), dimethoxypongapine (5) and the other is a triterpenoid (6). The pure compounds as well as petroleum ether, dichloromethane and ethyl acetate soluble fractions of crude methanolic extract were evaluated for bioactivities using established methods. In vitro antioxidant activity was studied by DPPH radical scavenging method using butylated hydroxyl anisole as standard. Among the pure compounds, kanugin and pongachromene showed significant antioxidant activity with the IC50 values of 27.20 ± 0.39 μg/mL and 43.53 ± 0.63 μg/ml, respectively as compared to the standard (23.87 ± 0.09 μg/ml), whereas karanjin, demethoxykanugin and dimethoxypongapine demonstrated moderate antioxidant activity. Mild thrombolytic activity was observed by different fractions with clot lysis ranging from 18.49 to 29.35% as compared to standard streptokinase (79.12%). The different solvent fractions and pure isolates showed very mild antimicrobial activity with zone of inhibition of 7.5 - 10.0 mm against the tested microorganisms using azithromycin and ketoconazole as standards. In the brine shrimp lethality bioassay, the dichloromethane, ethyl acetate, and methanol soluble fractions revealed significant lethality with LC50 values of 0.67 ± 0.05, 0.61 ± 0.13 and 0.56 ± 0.10 μg/ml, respectively as compared to standard tamoxifen (LC50 value 0.34 ± 0.09 μg/ml).
 Dhaka Univ. J. Pharm. Sci. 19(1): 1-8, 2020 (June)

Development of a high-performance liquid chromatography method with fluorescence detection for the routine quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen in plasma from breast cancer patients.

To date, several methods for the quantification of tamoxifen and its metabolites have been developed, most of which employ liquid chromatography tandem-mass spectrometry (LC-MS/MS). These methods are highly sensitive and reproducible, but are also time-consuming and require expensive equipment; one of their main disadvantages is matrix ionization effects. A more viable option, particularly in developing countries, is high-performance liquid chromatography coupled with UV or fluorescence detection. We developed and validated a method for simultaneous quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen based on high-performance liquid chromatography with fluorescence detection in a reverse-phase column. The method is rapid (16 min plus 5 min of column re-equilibrium), accurate (80-100%) and precise (0.23-6.00%), and does not require any additional irradiation process. Sample pretreatment consists of protein precipitation with acetonitrile under alkaline conditions, employing only 200 μL plasma. The validated method's wide range allowed quantification of steady-state levels in patients under standard tamoxifen treatment (20 mg/day). This assay is ready for application in clinical studies and routine quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen in healthcare institutions.

In vitro and in silico study of Aloe vera leaf extract against human breast cancer

Aloe vera leaf contains some bioactive compounds that have a strong binding affinity toward estrogen receptor as compared to standard drug tamoxifen. In this study, we have found that the IC50 of Aloe vera leaf extract against breast cancer cell line (MCF-7) is 23 µg/mL which is much lower than the IC50 (332 µg/mL) of Aloe vera leaf extract against non-cancerous cell line (NIH-3T3). We have also calculated the total concentration of phenolic acid (385.662 µg/mL), flavonoids (160.402 µg/mL) and alkaloids (276.754 µg/mL) in Aloe vera leaf extract. The free radical scavenging activity of Aloe vera leaf extract is 67% to 89% (at 50 to 300 µg/ml). Our virtual molecular docking study suggests that bioactive compounds like Aloe-emodin (−8.8 Kcal/mol), 7-hydroxy-2,5 dimethylchromone (−7.5 Kcal/mol), Beta-sitosterol (−7.3 Kcal/mol) etc. have a greater binding affinity toward estrogen alpha receptor as compared to standard drug Tamoxifen (−6.4 Kcal/mol).

Design, synthesis and biological evaluation of 3-(2-aminooxazol-5-yl)-2H-chromen-2-one derivatives

BackgroundIn view of wide range of biological activities of oxazole, a new series of oxazole analogues was synthesized and its chemical structures were confirmed by spectral data (Proton/Carbon-NMR, IR, MS etc.). The synthesized oxazole derivatives were screened for their antimicrobial and antiproliferative activities.Results and discussionThe antimicrobial activity was performed against selected fungal and bacterial strains using tube dilution method. The antiproliferative potential was evaluated against human colorectal carcinoma (HCT116) and oestrogen- positive human breast carcinoma (MCF7) cancer cell lines using Sulforhodamine B assay and, results were compared to standard drugs, 5-fluorouracil and tamoxifen, respectively.ConclusionThe performed antimicrobial activity indicated that compounds 3, 5, 6, 8 and 14 showed promising activity against selected microbial species. Antiproliferative screening found compound 14 to be the most potent compound against HCT116 (IC50 = 71.8 µM), whereas Compound 6 was the most potent against MCF7 (IC50 = 74.1 µM). Further, the molecular docking study has been carried to find out the interaction between active oxazole compounds with CDK8 (HCT116) and ER-α (MCF7) proteins indicated that compound 14 and 6 showed good dock score with better potency within the ATP binding pocket and may be used as a lead for rational drug designing of the anticancer molecule.

Design, Synthesis and Anti-breast Cancer Activity of Some Novel Substituted Isoxazoles as Anti-breast Cancer Agent.

A novel series of isoxazole (S21-S30) derivatives were designed, synthesized and screened for their anticancer activity against estrogen receptor-positive MCF-7 and negative MDA-MB-435 breast cancer cell lines. The synthesized derivative has the ability to inhibit the growth of the human breast cancer cell line at low concentrations. In vivo anticancer activity was performed on virgin female sprague dawley rats. The result shows that compound S23 has more selectivity and marked estrogen modulator activity than the standard tamoxifen.

Synthesis and Evaluation of Triazolyl Dihydropyrimidines as Potential Anticancer Agents

Novel N – triazolyl 3(a-f) and O-triazolyl (4a-f) derivatives of 4, 6-diaryl-1, 4-dihydropyrimidines were synthesized through mannich reaction. All compounds were characterized by physical and spectral data. These compounds were screened for in vitro efficiency in human breast cancer cell (MCF-7&MDA-MB-231) lines and found to have very good anti-proliferative activity.  Among all compounds of 4b, 3e, 4e endowed with lesser respective IC50 values of 31.94, 55.73, 55.03 µM in MCF-7 cells and 41.50, 35.28, 32.06 µM in MDA-MB 231 cells by MTT assay. In further studies, Compounds 4b, 3e, 4e were found to arrest cell growth at S phase in MCF-7 cells. In MDA-MB 231 cells, 4b, 4e were found to arrest the cells in S phase, and compound 3e found to arrest G2/M phase when compared to the standard drug tamoxifen, arrested S phase in MCF-7 cells and G0/G1 phase in MDA-MB 231 cells.

CYP2D6 as a treatment decision aid for ER-positive non-metastatic breast cancer patients: a systematic review with accompanying clinical practice guidelines.

Tamoxifen is one of the principal treatments for estrogen receptor (ER)-positive breast cancer. Unfortunately, between 30 and 50% of patients receiving this hormonal therapy relapse. Since CYP2D6 genetic variants have been reported to play an important role in survival outcomes after treatment with tamoxifen, this study sought to summarize and critically appraise the available scientific evidence on this topic. A systematic literature review was conducted to identify studies investigating associations between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment. Critical appraisal of the retrieved scientific evidence was performed, and recommendations were developed for CYP2D6 genetic testing in the context of tamoxifen therapy. Although conflicting literature exists, the majority of the current evidence points toward CYP2D6 genetic variation affecting survival outcomes after tamoxifen treatment. Of note, review of the CYP2D6 genotyping assays used in each of the studies revealed the importance of comprehensive genotyping strategies to accurately predict CYP2D6 metabolizer phenotypes. Critical appraisal of the literature provided evidence for the value of comprehensive CYP2D6 genotyping panels in guiding treatment decisions for non-metastatic ER-positive breast cancer patients. Based on this information, it is recommended that alternatives to standard tamoxifen treatments may be considered in CYP2D6 poor or intermediate metabolizers.

Cost-effectiveness of monitoring endoxifen levels in breast cancer patients adjuvantly treated with tamoxifen

PurposeBreast cancer is the most common malignancy in women worldwide. Recurrence rates in breast cancer are considered to be dependent on the serum concentration of endoxifen, the active metabolite of tamoxifen. The goal of this study is to investigate the cost-effectiveness of periodically monitoring serum concentrations of endoxifen in adjuvant estrogen receptor alfa (ERα) positive breast cancer patients treated with tamoxifen in the Netherlands.MethodsA Markov model with disease-free survival (DFS), recurrent disease (RD), and death states was constructed. The benefit of drug monitoring was modeled via a difference in the fraction of patients achieving adequate serum concentrations. Robustness of results to changes in model assumptions were tested through deterministic and probabilistic sensitivity analyses.ResultsMonitoring of endoxifen added 0.0115 quality-adjusted life-years (QALYs) and saved € 1564 per patient in the base case scenario. Deterministic sensitivity analysis demonstrated a large effect on the incremental cost-effectiveness ratio (ICER) of the differences in costs and utilities between the DFS and RD states. Probabilistic sensitivity analysis showed that the probability of cost-effectiveness at a willingness to pay of € 0 per quality-adjusted life-year (QALY) was 89.8%.ConclusionsBased on this model, monitoring of endoxifen in adjuvant ERα + breast cancer patients treated with tamoxifen is likely to add QALYs and save costs from a healthcare payer perspective. We advise clinicians to consider integrating serum endoxifen concentration monitoring into standard adjuvant tamoxifen treatment of ERα + breast cancer patients.

Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy.

Optimal management of the endometrium in patients with oestrogen receptor-positive breast cancer taking extended tamoxifen therapy (for 10 years) remains uncertain. A meta-analysis was performed to determine the cumulative risk ratio (RR) for endometrial malignancy following extended compared with standard tamoxifen treatment. A systematic review was undertaken to identify whether routine endometrial surveillance in patients receiving tamoxifen is associated with earlier detection and reduced incidence of endometrial malignancy. Two independent searches were undertaken in the Cochrane Library, PubMed and MEDLINE. A meta-analysis was performed of RCTs reporting on endometrial malignancy risk in extended tamoxifen therapy. A systematic review included prospective studies investigating the benefit of endometrial surveillance during tamoxifen therapy. Four RCTs reported on endometrial risk in extended tamoxifen therapy. The cumulative risk of endometrial malignancy increased twofold from 1·5 to 3·2 per cent with extended therapy compared with the standard 5 years of tamoxifen (RR 2·29, 95 per cent c.i. 1·60 to 3·28; P < 0·001). Four studies analysed the value of endometrial screening in 5-year cohorts. Endometrial cancer rates of up to 2 per cent were reported, which is higher than rates in the large extended tamoxifen trials. Extended adjuvant tamoxifen is associated with an increase in endometrial cancer. No clear benefit has been shown for routine endometrial surveillance in asymptomatic patients on tamoxifen therapy.

Design and synthesis of fluorescent symmetric bis-triazolylated-1,4-dihydropyridines as potent antibreast cancer agents

ABSTRACTHerein, we report the synthesis of fluorescent 1,4-dihydropyridine-linked bis-triazoles (2a–2n) through Hantzsch synthesis by the condensation of o/m-chloro-substituted benzaldehyde, ethyl 3-oxo-4(prop-2-yn-1-yloxy)butanoate, and ammonium acetate in the presence of Ba(NO3)2 as a catalyst followed by the click reaction of resultant Hantzsch product (1) with various aromatic as well as aliphatic azides. All the synthesized compounds were well characterized by 1H-NMR, 13C-NMR, FTIR, and HRMS spectral techniques. Antibreast cancer evaluation of all the synthesized derivatives revealed that the compounds 2f (IC50 = 7 ± 0.02 µM) and 2g (IC50 = 5 ± 0.03 µM) showed better anticancer activity (lower IC50) than the standard drug tamoxifen (IC50 = 11.2 ± 0.01 µM) against breast carcinoma (MDA-MB-231) cell line. The synthesized compounds were also screened against normal human embryonic kidney (HEK-293) cell line and found to be nontoxic. The fluorescent nature and cytotoxicity assay of these newly synthesized hybrids recommend their utility in tumor cell imaging.

Novel menadione hybrids: Synthesis, anticancer activity, and cell-based studies.

A series of novel menadione-based triazole hybrids were designed and synthesized by employing copper-catalyzed azide-alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data (1 H NMR, 13 C NMR, IR, and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU-145), cervical (Hela), breast (MCF-7), and mouse melanoma (B-16) using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity. Among the tested compounds, the triazoles 5 and 6 exhibited potent activity against all cell lines. In particular, compound 6 showed higher potency than the standard tamoxifen and parent menadione against MCF-7 cell line. Flow cytometric analysis revealed that compound 6 arrested cell cycle at G0/G1 phase and induced apoptotic cell death which was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin-V-FITC assay. Thus, compound 6 can be considered as lead molecule for further development as potent anticancer therapeutic agent.

Morpholine hydrazone scaffold: Synthesis, anticancer activity and docking studies

In this paper, synthesis and anticancer activities of morpholine hydrazones scaffold (1-17) thoroughly studied. Small series of morpholine hydrazones synthesized by treating 5-morpholinothiophene-2-carbaldehyde with different aryl hydrazides to form morpholine hydrazones scaffold (1-17). The in vitro anticancer potential of all these compounds was checked against human cancer cell lines like HepG2 (human hepatocellular liver carcinoma) and MCF-7 (human breast adenocarcinoma). Analogs 13 had similar substantial cytotoxic effects towards HepG2 with IC50 value 6.31±1.03μmol/L when compared with the standard Doxorubicin (IC50 value 6.00±0.80μmol/L); while compounds 5, 8 and 9 showed potent cytotoxicity against MCF-7 with IC50 value 7.08±0.42μmol/L, 1.26±0.34μmol/L and 11.22±0.22μmol/L respectively when compared with the standard Tamoxifen (IC50=11.00±0.40μmol/L). Molecular docking studies also performed to understand the binding interaction.

Efficacy of Pleurotus ostreatus (Jacq. Ex Fr.) P.kumm. on 7,12-dimethylbenz(a)anthracene induced mammary carcinogenesis in female Sprague-Dawley rats

Neoplastic growth of the breast is the most common malignancy in women worldwide and its incidence has increased in most countries. In this study, we have evaluated the efficacy of Pleurotus ostreatus (Jacq. Ex Fr.) P.kumm. (P. ostreatus) an edible mushroom on modulating levels of xenobiotic metabolizing enzymes, hormonal status of estrogen and progesterone receptor (ER/PR), protein expressions and histopathological analysis in 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinogenesis using a rat model. DMBA was induced by single subcutaneous injection at a dosage of 25mg in 1mL vehicle. The ethanolic extract of P. ostreatus (POEet) was administered orally at a concentration of 600mg/kg bwt as pre- and post-initiation stage of treatment throughout the experimental period which was also compared with standard tamoxifen (TAM) (10mg/kg bwt). At the end of 16 weeks, our results showed the elevated phase I and depleted phase II metabolizing enzymes, over expression of (ER/PR) and the expression pattern of the proteins such as fas, fasL, caspase 3, caspase 8, caspase 9, Bax were found to be down regulated whereas p53, Bcl2, cox-2 and cyclin D1 were markedly upregulated in DMBA-induced Sprague-Dawley rats, which were significantly reversed on P. ostreatus administration. Moreover, pre-treatment with P. ostreatus showed improved response when compared to that of posttreatment. Based on scientific appraisal, we conclude that the dietary consumption of P. ostreatus might offer maximum protection against DMBA-induced mammary carcinogenesis and improving human health if used as a regular basis. Focal points•Benchside○ The potential of Pleurotus ostreatus on DMBA induced rat mammary carcinogenesis were determined by the analysis of xenobiotic metabolizing enzymes, hormonal status of ER/PR, as well as the expression of protein using western blotting techniques and histological examination of liver and mammary tissues.•Bedside○ The pharmaceutical potential of P. ostreatus are analysed for is markedly available, edible one with high protein as well as fiber with low fat content and cost effective for patient convenience.•Industry○ Mushrooms are considered as a nutraceutical functional food which can contain enriched prolific produced of novel “mycochemicals” responsible for the human health potential on various diseases and malignancies.•Community○ Standardization and refinement of mycochemical from mushrooms were help to develop the new novel active compounds which contribute for better health and also help to reduce disease burden.•Regulatory agencies○ The P. ostreatus contain several bioactive compounds which might be the key factor for the anticancer effect. This will need to be taken for labeling and pattering the compounds and tested in clinical trials.