Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs

Mahmud Hasan, Mohamed Akmal Marzouk, Saugat Adhikari, Thomas D. Wright, Benton P. Miller, Margarite D. Matossian, Steven Elliott, Maryl Wright, Madlin Alzoubi, Bridgette M. Collins-Burow, Matthew E. Burow, Ulrike Holzgrabe, Darius P. Zlotos, Robert Stratford Jr., Paula A. Witt-Enderby

Research output: Contribution to journalArticle

Abstract

Tamoxifen is used to prevent and treat estrogen receptor-positive (ER1) 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 (IC50 5 4-8 mM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 5 80-211 mM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 5 181-304 mM; efficacy ∼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 kB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.

Original languageEnglish (US)
Pages (from-to)272-296
Number of pages25
JournalMolecular Pharmacology
DOIs
StatePublished - Jan 1 2019

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Melatonin
Tamoxifen
Pharmacokinetics
Pharmacology
Breast Neoplasms
Pharmaceutical Preparations
MCF-7 Cells
Inhibitory Concentration 50
1-Phosphatidylinositol 4-Kinase
Estrogen Receptor alpha
Cell Survival
MAP Kinase Kinase 2
Melatonin Receptors
Triple Negative Breast Neoplasms
Cell Line
Uterine Neoplasms
Heterografts
Estrogen Receptors
Biological Availability
Cell Movement

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Hasan, M., Marzouk, M. A., Adhikari, S., Wright, T. D., Miller, B. P., Matossian, M. D., ... Witt-Enderby, P. A. (2019). Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs. Molecular Pharmacology, 272-296. https://doi.org/10.1124/mol.119.116202

Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs. / Hasan, Mahmud; Marzouk, Mohamed Akmal; Adhikari, Saugat; Wright, Thomas D.; Miller, Benton P.; Matossian, Margarite D.; Elliott, Steven; Wright, Maryl; Alzoubi, Madlin; Collins-Burow, Bridgette M.; Burow, Matthew E.; Holzgrabe, Ulrike; Zlotos, Darius P.; Stratford Jr., Robert; Witt-Enderby, Paula A.

In: Molecular Pharmacology, 01.01.2019, p. 272-296.

Research output: Contribution to journalArticle

Hasan, M, Marzouk, MA, Adhikari, S, Wright, TD, Miller, BP, Matossian, MD, Elliott, S, Wright, M, Alzoubi, M, Collins-Burow, BM, Burow, ME, Holzgrabe, U, Zlotos, DP, Stratford Jr., R & Witt-Enderby, PA 2019, 'Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs', Molecular Pharmacology, pp. 272-296. https://doi.org/10.1124/mol.119.116202
Hasan, Mahmud ; Marzouk, Mohamed Akmal ; Adhikari, Saugat ; Wright, Thomas D. ; Miller, Benton P. ; Matossian, Margarite D. ; Elliott, Steven ; Wright, Maryl ; Alzoubi, Madlin ; Collins-Burow, Bridgette M. ; Burow, Matthew E. ; Holzgrabe, Ulrike ; Zlotos, Darius P. ; Stratford Jr., Robert ; Witt-Enderby, Paula A. / Pharmacological, mechanistic, and pharmacokinetic assessment of novel_ melatonin-tamoxifen drug conjugates as breast cancer drugs. In: Molecular Pharmacology. 2019 ; pp. 272-296.
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N2 - Tamoxifen is used to prevent and treat estrogen receptor-positive (ER1) 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 (IC50 5 4-8 mM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 5 80-211 mM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 5 181-304 mM; efficacy ∼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 kB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.

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