DOCSLIB.ORG

In Silico Prediction of Heliannuol A, B, C, D, and E Compounds on Estrogen Receptor Β Agonists

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
In Silico Prediction of Heliannuol A, B, C, D, and E Compounds on Estrogen Receptor Β Agonists Indonesian Journal of Cancer Chemoprevention, February 2021 ISSN: 2088–0197 e-ISSN: 2355-8989 In Silico Prediction of Heliannuol A, B, C, D, and E Compounds on Estrogen Receptor β Agonists Roihatul Mutiah, Alif Firman Firdausy, Yen Yen Ari Indrawijaya, Hibbatullah* Department of Pharmacy, Faculty of Medical and Health Sciences, Maulana Malik Ibrahim State Islamic University of Malang, Indonesia Abstract Heliannuols has a benzoxepine ring that produces anticancer activity by the inhibition mechanism of phosphoinositide 3 kinases (PI3K). Heliannuols are a compound that can be found in the leaves of sunflower Helianthus( annuus L.). The purpose of this study is to predict interactions, toxicity, physicochemical, and pharmacokinetics of Heliannuol A, B, C, D, and E based in silico as candidate anticancer drugs. Estrogen receptor beta (ERβ) is a new potential therapy for glioma with an antiproliferative effect. Ligands agonist ERβ have the potential activity to inhibit the proliferation of glioma cells and the discovery of this ligand has opened new therapy through the ERβ to prolong survival in cancer patients. Prediction of physicochemical properties based on Lipinski rules and penetrate in the blood-brain barrier. Receptor validation shows that 2I0G(A) has a smaller RMSD value than 2I0G(B), receptor validation is valid if the RMSD value less than 2. The result of molecular docking shows that Heliannuols comply with Lipinski rules and have low toxicity. Heliannuols also have a similar amino acid with comparison drug (Erteberel), but the rerank score of Erteberel still lower than Heliannuols. Keywords: Helianthus annuus, Heliannuols, estrogen receptor β (ERβ), in silico, toxicity. INTRODUCTION using HPLC with hexane and ethyl acetate solvents (Macias, et al., 1994; Macias, et al., 2000; Macias, Sunflower plant (Helianthus annuus L.) has et al., 2002). The new anticancer treatment therapy many chemical compounds, especially in the leaves involves estrogen receptor beta-agonists (ERβ) of this plant containing monoterpene, diterpene, by the pathway of inhibiting cancer growth and alkaloids, phenols, and lactone sesquiterpenes anticancer therapy with estrogen receptors can (Ceccarini, 2004). Heliannuols are one of the reduce glioma cell proliferation (Sareddy, et al., sesquiterpenes which has a benzoxepine ring and 2012; Sareddy and Vadlamudi, 2015). anticancer activity produced by the inhibition ERβ has quite a different function mechanism of phosphoinositide 3 kinases (PI3K) from ERα, ERβ has antiproliferative action and (Ghantous, et al., 2010; Hefron, et al., 2011; Kuntala, et al., 2017; Ren, et al., 2003). Heliannuol A, B, C, D, and E were obtained from sunflower Submitted: September 29, 2020 Revised: February 9, 2021 leaves that had been immersed in water for 24 h and Accepted: February 15, 2021 extracted with chloroform (CH2Cl2) then observed *Corresponding author: [email protected] 37 Mutiah, et al., 2021 Indones. J. Cancer Chemoprevent., 12(1), 37-45 overexpression of ERβ can reduce proliferation in and Molegro Virtual Docker 6 (Lisensi expires on: cancer cells (Strom, et al., 2004; Hartman, et al., January 01, 2099). 2009; Nilsson, et al., 2011). This research focuses on estrogen receptor beta agonists because it has the Target and Template Selection potential as an antitumor therapy agent by activating The target of this research is the estrogen beta subtypes and preventing proliferative effects receptor beta 2I0G from Protein Data Bank (https:// on cancer. Ligands that are included as estrogen www.rcsb.org). The test compounds of this research receptor beta-agonists that have the potential activity are Heliannuol A, B, C, D, and E where the SMILES to inhibit the proliferation of glioma cells are DPN code from Chem Bio Draw 12.0 and the Erteberel (Diarylpropionitrile), MFF101, Liquiri-tigenin, and SMILES code from PubChem. LY500307 (comparison drug (Erteberel)) (Sareddy, et al., 2012; Sareddy and Vadlamudi, 2015). Prediction of Physicochemical, Erteberel is one of the agonists ERβ that has high Pharmacokinetic, and Toxicity Properties potential in reducing glioma cell proliferation and Prediction of physicochemical properties it can penetrate the blood-brain barrier (Sareddy, et using the pkCSM online tool and the Protox II al., 2016). The discovery of a specific agonists ERβ online tool by entering the SMILES code of the provided naturally has opened the development of compound. The prediction of physicochemical new therapies through the estrogen receptor beta to properties is based on Lipinski’s rules and the prolong survival in cancer patients (Sareddy and ability of compounds to penetrate the brain Vadlamudi, 2015). barrier membrane. Lipinski’s rules use to evaluate Based on the research by Sareddy, et al. compounds that have pharmacological activity with (2012) show that ERβ pathway activation is a predictable physical and chemical properties as potential therapeutic target for glioma because drug candidates for humans. While the prediction ERβ agonists are under clinical trials and are well of pharmacokinetic properties using the online tolerated with fewer side effects. The use of ERβ pkCSM tool is based on the absorption, distribution, as a therapeutic agent can be extended to clinical metabolism, and excretion parameters. Toxicity use and is predicted to be a new class of drugs prediction using the pkCSM online tool and the for treating glioma. Future studies examining the Protox II online tool based on several parameters mechanism of ERβ in cancer progression will be and toxicity classes according to the Globally useful for maximizing treatment using ERβ natural Harmonized System (GHS). ligands (Sareddy and Vadlamudi, 2015). The purpose of this study was to determine the activity Molecular Docking of Heliannuols on estrogen receptor beta and the Molecular docking using Molegro Virtual lack of information on estrogen receptor beta- Docker 6.0 to know the interaction between the agonists as therapeutic agents in cancer patients, test compound and the receptor. 2D structures of encouraging researchers to compile this study. Heliannuol A, B, C, D, and E were drawn using Chem Draw Ultra 12.0 and to know the SMILES MATERIALS AND METHODS code of the test compounds then 3D structures were made using Avogadro and energy minimization Software was performed. Validation of molecular docking This research uses Chem Bio Draw Ultra ERβ (2I0G) using Molegro Virtual Docker 6.0 and 12.0 application, Avogadro, pkCSM online tool, a docking simulation process was also performed. Protox II online tool (accessed on January 2020), Validation of molecular docking result is the Root 38 Indonesian Journal of Cancer Chemoprevention, February 2021 ISSN: 2088–0197 e-ISSN: 2355-8989 Mean Square Deviation (RMSD), the docking of compounds to penetrate the brain barrier mem- simulation process can be run if the RMSD value brane, and toxicity are shown in Table 1. was less than 2Å. The parameters used in docking The results of physicochemical prediction simulation include rerank score, bond distance, and show that all compounds comply with Lipinski type of interaction. rules, it can be predicted that all compound easy to absorption and has good permeability. The result RESULTS of TPSA showed that all compounds have a TPSA value of less than 80, it can be predicted that all Prediction of Physicochemical Properties compounds could penetrate the brain barrier mem- and Toxicity brane (Hughes, 2008). Heliannuol A, B, and C are Prediction of physicochemical properties in toxicity class 4 with Lethal Dose (LD50) 300-2000 using Lipinski rules of five with several parameters mg/kg. Heliannuol D and Erteberel are in toxicity includes molecular weight, the partition coefficient class 5 with LD50 2000-5000 mg/kg. Heliannuol A, of octanol/water (log P), Hydrogen Bond Donors B, C, D, E, and Erteberel were predicted to be non- (HBD), and Hydrogen Bond Acceptors (HBA). toxic in the AMES Mutagenic test, not toxic in the Topological Polar Surface Area (TPSA) also a Hepatotoxicity test, and did not cause skin irritation parameter to determine compound can penetrate in the Skin Sensitization test. the brain barrier membrane (Kelder, et al., 1999). The physicochemical test was used to predict that Prediction of Pharmacokinetic Properties the compound has good permeability, high absorp- Prediction of pharmacokinetic properties tion, and can penetrate the blood-brain barrier. The is based on the prediction of absorption, distribu- results of physicochemical properties, the ability tion, metabolism, and excretion (ADME) using the Table 1. Prediction of physicochemical and toxicity. Description: *pkCSM online tool; **Protox II online tool. pkCSM online tool. The results of the prediction of website (http://biosig.uni-melb.edu.au/pkcsm/the- pharmacokinetic properties are shown in Table 2. ory), the compound has a high skin permeability if The result from the prediction of phar- the Log value of Kp>-2.5 cm/h, and all compound macokinetic properties shows ADME of the com- are predicted have high skin permeability. Caco2 pound, in this research shows that all compound permeability is good if the Papp value>0.90 cm/s is predicted to have good intestinal absorption and all compounds are predicted to have good per- with the value is more than 80% (Chander, et al., meability. Heliannuol C and E do not include as 2017). According to the pkCSM online tool page Pgp substrates, then they are not predicted to be 39 Mutiah, et al., 2021 Indones. J. Cancer Chemoprevent., 12(1), 37-45 Table 2. Prediction of pharmacokinetic properties. Description: Vdss (Volume of Distribution at Steady State); BBB (Blood Brain Barrier); CNS (Central Nervous Sys- tem); CYP2D6 (Cytochrome P2D); CYP3A4 (Cytochrome 3A4); CYP1A2 (Cytochrome 1A2); CYP2C19 (Cyto- chrome 2C19); CYP2C9 (Cytochrome 2C9); Renal OCT2 (Renal Organic Cation Transporter 2). *The highest value of comparative drugs; **The highest value of the first test compound; +The second highest value of the test compound; ++Different result from other. removed from the target cell (Chakraborty and Ra- high if the Log Vdss value >0.45, all compound makrishnan, 2016). Heliannuol A, B, C, D, E, and has good distribution volume.
Load more

Recommended publications
  • Erteberel (LY500307) Product Data Sheet
    Product Name: Erteberel (LY500307) Revision Date: 01/10/2021 Product Data Sheet Erteberel (LY500307) Cat. No.: B1518 CAS No.: 533884-09-2 Formula: C18H18O3 M.Wt: 282.33 Synonyms: Target: Endocrinology and Hormones Pathway: Estrogen/progestogen Receptor Storage: Store at -20°C Solvent & Solubility insoluble in H2O; ≥14.1 mg/mL in DMSO; ≥48.3 mg/mL in EtOH Mass Solvent 1mg 5mg 10mg Preparing Concentration In Vitro Stock Solutions 1 mM 3.5420 mL 17.7098 mL 35.4195 mL 5 mM 0.7084 mL 3.5420 mL 7.0839 mL 10 mM 0.3542 mL 1.7710 mL 3.5420 mL Please refer to the solubility information to select the appropriate solvent. Biological Activity Shortsummary ERβ agonist, potent and selective IC₅₀ & Target Cell Viability Assay Cell Line: Human prostate cancer cell line (PC-3 cells) Preparation method： The solubility of this compound in DMSO is >10 mM. General tips for obtaining In Vitro a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months. Reacting conditions: N/A 1 | www.apexbt.com Applications: Erteberel showed potent and selective binding affinity for ERβ with EC50 value of 0.66 nM [1]. Animal experiment Animal models: Male and female rat fertility and rat and rabbit embryo-fetal development model Dosage form: 0.03 to 10 mg/kg/day for rats, or 1 to 25 mg/kg/day for rabbits, oral gavage, for 2 or 10 weeks Applications: There were no-observed adverse effect levels following LY500307 In Vivo administration of 1 mg/kg/day for male rat fertility, 0.3 mg/kg/day for female rat fertility and embryo-fetal development, and 25 mg/kg/day for rabbit embryo-fetal development [2].
    [Show full text]
  • Supplementary Information
    Supplementary Information Network-based Drug Repurposing for Novel Coronavirus 2019-nCoV Yadi Zhou1,#, Yuan Hou1,#, Jiayu Shen1, Yin Huang1, William Martin1, Feixiong Cheng1-3,* 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA 3Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA #Equal contribution *Correspondence to: Feixiong Cheng, PhD Lerner Research Institute Cleveland Clinic Tel: +1-216-444-7654; Fax: +1-216-636-0009 Email: [email protected] Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. Supplementary Table S2. Protein sequence identities across 5 protein regions in 15 coronaviruses. Supplementary Table S3. HCoV-associated host proteins with references. Supplementary Table S4. Repurposable drugs predicted by network-based approaches. Supplementary Table S5. Network proximity results for 2,938 drugs against pan-human coronavirus (CoV) and individual CoVs. Supplementary Table S6. Network-predicted drug combinations for all the drug pairs from the top 16 high-confidence repurposable drugs. 1 Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. GenBank ID Coronavirus Identity % Host Location discovered MN908947 2019-nCoV[Wuhan-Hu-1] 100 Human China MN938384 2019-nCoV[HKU-SZ-002a] 99.99 Human China MN975262
    [Show full text]
  • WHO Drug Information Vol
    WHO Drug Information Vol. 24, No. 4, 2010 World Health Organization WHO Drug Information Contents WHO Prequalification Sitaxentan: worldwide withdrawal 307 Programmes Sibutramine: suspension of sales 307 Sibutramine-containing medicines: WHO Prequalification of Medicines withdrawal 308 Programme: survey of service Testosterone transdermal patch: quality provided to manufacturers 293 withdrawal of extension of WHO initiates pilot prequalification of indication application 308 active pharmaceutical ingredients 297 Aliskiren/valsartan: withdrawal of New on-line database for WHO marketing authorization application 308 prequalified vaccines 298 Mometasone furoate/formoterol fumarate: withdrawal of marketing Safety and Efficacy Issues authorization application 309 EMA and US FDA extend confidentiality H1N1 influenza vaccine: narcolepsy 299 arrangements indefinitely 309 Statins: interstitial lung disease 299 Tocilizumab: risk of fatal anaphylaxis 300 Recent Publications, Pioglitazone: potential bladder cancer 301 Information and Events Angiotensin receptor blockers and US Government to share patents with cancer: safety review 301 Medicines Patent Pool 310 GnRH agonists, diabetes and cardio- Clinical trials and global medicines vascular disease 301 development 310 Gadolinium-based contrast agents: Evaluation of future nanomedicines 311 kidney dysfunction 302 Reporting on opioid inaccessibility 311 Lamotrigine: aseptic meningitis Tinzaparin sodium: renal Impairment in elderly 303 Consultation Documents Tamoxifen: drug interactions involving The
    [Show full text]
  • TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub
    US 20200187851A1TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0187851 A1 Offenbacher et al. (43 ) Pub . Date : Jun . 18 , 2020 ( 54 ) PERIODONTAL DISEASE STRATIFICATION (52 ) U.S. CI. AND USES THEREOF CPC A61B 5/4552 (2013.01 ) ; G16H 20/10 ( 71) Applicant: The University of North Carolina at ( 2018.01) ; A61B 5/7275 ( 2013.01) ; A61B Chapel Hill , Chapel Hill , NC (US ) 5/7264 ( 2013.01 ) ( 72 ) Inventors: Steven Offenbacher, Chapel Hill , NC (US ) ; Thiago Morelli , Durham , NC ( 57 ) ABSTRACT (US ) ; Kevin Lee Moss, Graham , NC ( US ) ; James Douglas Beck , Chapel Described herein are methods of classifying periodontal Hill , NC (US ) patients and individual teeth . For example , disclosed is a method of diagnosing periodontal disease and / or risk of ( 21) Appl. No .: 16 /713,874 tooth loss in a subject that involves classifying teeth into one of 7 classes of periodontal disease. The method can include ( 22 ) Filed : Dec. 13 , 2019 the step of performing a dental examination on a patient and Related U.S. Application Data determining a periodontal profile class ( PPC ) . The method can further include the step of determining for each tooth a ( 60 ) Provisional application No.62 / 780,675 , filed on Dec. Tooth Profile Class ( TPC ) . The PPC and TPC can be used 17 , 2018 together to generate a composite risk score for an individual, which is referred to herein as the Index of Periodontal Risk Publication Classification ( IPR ) . In some embodiments , each stage of the disclosed (51 ) Int. Cl. PPC system is characterized by unique single nucleotide A61B 5/00 ( 2006.01 ) polymorphisms (SNPs ) associated with unique pathways , G16H 20/10 ( 2006.01 ) identifying unique druggable targets for each stage .
    [Show full text]
  • New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection
    Chapter 12 New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection Manuela Cristina Russu and Alexandra Cristina Antonescu Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.74332 Abstract Perimenopause is a mandatory period in women’s life, when the medical staff may initiate hormone therapy with sex steroids for the delay of brain aging and neurodegenerative diseases, during the so-called “window of opportunity.” Animals’ models are helpful to sustain the still controversial results of human clinical observational and/or randomized controlled studies. Estrogens, progesterone, and androgens, with their nuclear and mem- brane receptors, genes, and epigenetics, with their connections to cholinergic, GABAergic, serotoninergic, and glutamatergic systems are involved in women’snormalbrainorin brain’s pathology. The sex steroids are active through direct and/or indirect mechanisms to modulate and/or to protect brain plasticity, and vessels network, fuel metabolism—glucose, ketones, ATP, to reduce insulin resistance, and inflammation of the aging brain through blood-brain barrier disruption, microglial aberrant activation, and neural cell survival/loss. Keywords: perimenopause, “window” of opportunity, neuroprotection, sex steroid hormones 1. Introduction The months/years of perimenopause represent an important moment during women’saging, when sex steroids and their receptors decline are evident in the hippocampal and cortical neu- rons, after estrogen exposure during the reproductive years. The sex steroid hormones decline is associated/acts synergic to other factors as hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, vitamin B12/folate deficiency, depression, and traumatic brain injury to promote diverse pathological mechanisms involved in brain aging, memory impairment, and AD.
    [Show full text]
  • Estrogen Receptor Beta Is a Negative Regulator of Mammary Cell Proliferation Xiaozheng Song University of Vermont
    University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2014 Estrogen Receptor Beta Is A Negative Regulator Of Mammary Cell Proliferation Xiaozheng Song University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Animal Sciences Commons, and the Molecular Biology Commons Recommended Citation Song, Xiaozheng, "Estrogen Receptor Beta Is A Negative Regulator Of Mammary Cell Proliferation" (2014). Graduate College Dissertations and Theses. 259. https://scholarworks.uvm.edu/graddis/259 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. ESTROGEN RECEPTOR BETA IS A NEGATIVE REGULATOR OF MAMMARY CELL PROLIFERATION A Dissertation Presented by Xiaozheng Song to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Animal Science October, 2014 Accepted by the Faculty of the Graduate College, The University of Vermont, in partial fulfillment of the requirements for the degree of Doctor of Philosophy, specializing in Animal Science. Dissertation Examination Committee: ____________________________________ Advisor Zhongzong Pan Ph.D. ____________________________________ Co-Advisor Andre-Denis Wright Ph.D. ____________________________________ Rona Delay, Ph.D. ____________________________________ David Kerr, Ph.D. ____________________________________ Chairperson Karen M. Lounsbury, Ph. D. ____________________________________ Dean, Graduate College Cynthia J. Forehand, Ph.D. Date: May 5, 2014 ABSTRACT The mammary gland cell growth and differentiation are under the control of both systemic hormones and locally produced growth factors.
    [Show full text]
  • Estriol Therapy for Autoimmune and Neurodegenerative Diseases and Disorders
    (19) TZZ¥Z__T (11) EP 3 045 177 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 20.07.2016 Bulletin 2016/29 A61K 31/565 (2006.01) A61K 31/566 (2006.01) A61K 31/568 (2006.01) A61K 45/06 (2006.01) (2006.01) (2006.01) (21) Application number: 16000349.7 A61K 31/785 A61P 25/00 (22) Date of filing: 26.09.2006 (84) Designated Contracting States: (72) Inventor: Voskuhl, Rhonda R. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Los Angeles, CA 90024 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR (74) Representative: Müller-Boré & Partner Patentanwälte PartG mbB (30) Priority: 26.09.2005 US 720972 P Friedenheimer Brücke 21 26.07.2006 US 833527 P 80639 München (DE) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: This application was filed on 11-02-2016 as a 13005320.0 / 2 698 167 divisional application to the application mentioned 06815626.4 / 1 929 291 under INID code 62. (71) Applicant: The Regents of the University of California Oakland, CA 94607 (US) (54) ESTRIOL THERAPY FOR AUTOIMMUNE AND NEURODEGENERATIVE DISEASES AND DISORDERS (57) The present invention relates to a dosage from comprising estriol and glatiramer acetate polymer-1 for use in the treatment of multiple sclerosis (MS), as well as to a kit comprising estriol and glatiramer acetate polymer-1. EP 3 045 177 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 045 177 A1 Description [0001] This invention was made with Government support under Grant No.
    [Show full text]
  • Decreases Breast Cancer Cell Survival by Regulating the IRE1&Sol
    Oncogene (2015) 34, 4130–4141 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE ERβ decreases breast cancer cell survival by regulating the IRE1/XBP-1 pathway G Rajapaksa1, F Nikolos1, I Bado1, R Clarke2, J-Å Gustafsson1 and C Thomas1 Unfolded protein response (UPR) is an adaptive reaction that allows cancer cells to survive endoplasmic reticulum (EnR) stress that is often induced in the tumor microenvironment because of inadequate vascularization. Previous studies report an association between activation of the UPR and reduced sensitivity to antiestrogens and chemotherapeutics in estrogen receptor α (ERα)- positive and triple-negative breast cancers, respectively. ERα has been shown to regulate the expression of a key mediator of the EnR stress response, the X-box-binding protein-1 (XBP-1). Although network prediction models have associated ERβ with the EnR stress response, its role as regulator of the UPR has not been experimentally tested. Here, upregulation of wild-type ERβ (ERβ1) or treatment with ERβ agonists enhanced apoptosis in breast cancer cells in the presence of pharmacological inducers of EnR stress. Targeting the BCL-2 to the EnR of the ERβ1-expressing cells prevented the apoptosis induced by EnR stress but not by non-EnR stress apoptotic stimuli indicating that ERβ1 promotes EnR stress-regulated apoptosis. Downregulation of inositol-requiring kinase 1α (IRE1α) and decreased splicing of XBP-1 were associated with the decreased survival of the EnR-stressed ERβ1-expressing cells. ERβ1 was found to repress the IRE1 pathway of the UPR by inducing degradation of IRE1α.
    [Show full text]
  • Targeting Estrogen Receptor Subtypes (Era and Erb) with Selective ER Modulators in Ovarian Cancer
    KK-L CHAN and others Estrogen receptor subtypes in 221:2 325–336 Research ovarian cancer Targeting estrogen receptor subtypes (ERa and ERb) with selective ER modulators in ovarian cancer Karen Kar-Loen Chan, Thomas Ho-Yin Leung, David Wai Chan, Na Wei, Correspondence Grace Tak-Yi Lau, Stephanie Si Liu, Michelle K-Y Siu and Hextan Yuen-Sheung Ngan should be addressed to K K-L Chan Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Email 6/F Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong [email protected] Abstract Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is Key Words an attractive treatment option because of its relatively few side effects. However, estrogen " estrogen receptors was previously shown to have opposite effects in tumors expressing ERa compared with ERb, " SERMS indicating that the two receptor subtypes may have opposing effects. This may explain the " ovarian cancer modest response to nonselective estrogen inhibition in clinical practice. In this study, we " hormonal treatment aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. Sodium 30-(1-(phenylaminocarbonyl)-3,4- Journal of Endocrinology tetrazolium)-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) assay revealed that treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H- pyrazole dihydrochloride (MPP) (ERa antagonist) or 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) (ERb agonist) significantly suppressed cell growth in both cell lines.
    [Show full text]
  • Mitochondrial Estrogen Receptors Alter Mitochondrial Priming and Response to Endocrine Therapy in Breast Cancer Cells
    Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells. Ozgur Kutuk ( [email protected] ) Başkent University, Adana Dr. Turgut Noyan Medical and Research Center https://orcid.org/0000-0001- 9854-7220 Bahriye Karakas Sabanci University Yeliz Aka Baskent University Asli Giray Alanya Alaaddin Keykubat University Huveyda Basaga Sabanci University Ufuk Acikbas Baskent University Ozgur Gul Bilgi University Sehime Gulsun Temel Uludag University Article Keywords: breast cancer, BH3, Estrogen receptor, mitochondrial estrogen signaling Posted Date: February 5th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-139821/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/29 Abstract Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of rst-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 proling technology, in particular dynamic BH3 proling can predict the response to endocrine therapy agents as well as development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunouorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents.
    [Show full text]
  • Mitochondrial Estrogen Receptors Alter Mitochondrial Priming and Response to Endocrine Therapy in Breast Cancer Cells
    www.nature.com/cddiscovery ARTICLE OPEN Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells ✉ Bahriye Karakas1, Yeliz Aka2, Asli Giray3, Sehime Gulsun Temel4,5,6, Ufuk Acikbas2, Huveyda Basaga1, Ozgur Gul7 and Ozgur Kutuk 2 © The Author(s) 2021 Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-β subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-β in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-β in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-β in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-β can be successfully targeted by the selective ER-β agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.
    [Show full text]
  • G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives
    cells Review G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives Richard A. Pepermans 1, Geetanjali Sharma 1,2 and Eric R. Prossnitz 1,2,3,* 1 Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; [email protected] (R.A.P.); [email protected] (G.S.) 2 Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA 3 University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA * Correspondence: [email protected]; Tel.: +1-505-272-5647 Abstract: Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1.
    [Show full text]