PMID- 31221824
OWN - NLM
STAT- MEDLINE
DCOM- 20191211
LR  - 20210816
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 96
IP  - 2
DP  - 2019 Aug
TI  - Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel 
      Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs.
PG  - 272-296
LID - 10.1124/mol.119.116202 [doi]
AB  - Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast 
      cancer (BC); however, its chronic use can increase uterine cancer risk and induce 
      tamoxifen resistance. Novel melatonin-tamoxifen drug conjugates may be promising 
      to treat BC and may help offset the adverse effects of tamoxifen usage alone due 
      to the presence of melatonin. We synthesized and screened five drug conjugates 
      (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, 
      tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) 
      viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and 
      estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable 
      pharmacological characteristics with respect to binding profiles (affinity for 
      ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and 
      migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 
      were further assessed for their actions against tamoxifen-resistant MCF-7 cells 
      and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for 
      their mechanisms of action using selective mitogen-activated protein kinase 
      kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 
      inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC(50) = 4-8 muM) 
      and efficacy ( approximately 90% inhibition of viability and migration) but demonstrated 
      increased potency (IC(50) = 80-211 muM) and efficacy ( approximately 140% inhibition) to inhibit 
      migration versus cell viability (IC(50) = 181-304 mM; efficacy  approximately 80% inhibition) 
      in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 
      having greater bioavailability than C5. Further assessment of C4 and C5 
      demonstrates that they create novel pharmacophores within each BC cell that is 
      context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear 
      factor kappaB. These melatonin-tamoxifen drug conjugates show promise as novel 
      anticancer drugs and further preclinical and clinical evaluation is warranted.
CI  - Copyright (c) 2019 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Hasan, Mahmud
AU  - Hasan M
AUID- ORCID: 0000-0003-0192-6166
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Marzouk, Mohamed Akmal
AU  - Marzouk MA
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Adhikari, Saugat
AU  - Adhikari S
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Wright, Thomas D
AU  - Wright TD
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Miller, Benton P
AU  - Miller BP
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Matossian, Margarite D
AU  - Matossian MD
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Elliott, Steven
AU  - Elliott S
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Wright, Maryl
AU  - Wright M
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Alzoubi, Madlin
AU  - Alzoubi M
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Collins-Burow, Bridgette M
AU  - Collins-Burow BM
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Burow, Matthew E
AU  - Burow ME
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Holzgrabe, Ulrike
AU  - Holzgrabe U
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Zlotos, Darius P
AU  - Zlotos DP
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Stratford, Robert E
AU  - Stratford RE
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.).
FAU - Witt-Enderby, Paula A
AU  - Witt-Enderby PA
AUID- ORCID: 0000-0002-1844-4457
AD  - Division of Pharmaceutical, Administrative and Social Sciences, Duquesne 
      University, Pittsburgh, Pennsylvania (M.H., T.D.W., B.P.M., P.A.W.-E.); 
      Department of Pharmaceutical Chemistry, German University in Cairo, New Cairo 
      City, Cairo, Egypt (M.A.M., D.P.Z.); Purdue University, West Lafayette, Indiana 
      (S.A.); Section of Hematology and Medical Oncology, Department of Medicine, 
      Tulane Cancer Center, Tulane University School of Medicine, New Orleans, 
      Louisiana (M.D.M., S.E., M.W., M.A., B.M.C.-B., M.E.B.); Institute of Pharmacy 
      and Food Chemistry, University of Wuerzburg, Am Hubland, Wuerzburg, Germany 
      (U.H.); Indiana University School of Medicine, Indianapolis, Indiana (R.E.S.); 
      and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, 
      Pennsylvania (P.A.W.-E.) wittp@duq.edu.
LA  - eng
GR  - R01 CA174785/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190620
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Antineoplastic Agents)
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Receptor, Melatonin, MT1)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/pharmacokinetics/pharmacology
MH  - Biological Availability
MH  - Breast Neoplasms/*drug therapy/metabolism
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Survival/drug effects
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Estrogen Receptor alpha/*metabolism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects
MH  - MCF-7 Cells
MH  - Melatonin/*administration & dosage/pharmacokinetics/pharmacology
MH  - Mice
MH  - Receptor, Melatonin, MT1/*metabolism
MH  - Tamoxifen/*administration & dosage/pharmacokinetics/pharmacology
PMC - PMC6666385
EDAT- 2019/06/22 06:00
MHDA- 2019/12/18 06:00
PMCR- 2020/08/01
CRDT- 2019/06/22 06:00
PHST- 2019/02/11 00:00 [received]
PHST- 2019/06/07 00:00 [accepted]
PHST- 2019/06/22 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/06/22 06:00 [entrez]
PHST- 2020/08/01 00:00 [pmc-release]
AID - mol.119.116202 [pii]
AID - MOL_116202 [pii]
AID - 10.1124/mol.119.116202 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2019 Aug;96(2):272-296. doi: 10.1124/mol.119.116202. Epub 2019 Jun 
      20.