Defense Date

9-4-2020

Graduation Date

Fall 12-18-2020

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Paula A. Witt-Enderby

Committee Member

David A. Johnson

Committee Member

Jane E. Cavanaugh

Committee Member

Lauren A. O’Donnell

Committee Member

Robert E. Stratford

Keywords

melatonin-tamoxifen drug conjugates, triple negative breast cancer, tamoxifen resistant breast cancer, MEK1/2, MEK5, PI3 kinase, estrogen receptors, melatonin receptors

Abstract

Tamoxifen is a first-generation selective estrogen receptor modulator, which reduces the risk of both invasive and non-invasive breast cancer (BC) as well as tumor recurrence in several clinical trials. However, chronic use of tamoxifen can increase uterine cancer risk and induce tamoxifen resistance. In past studies, melatonin alone reversed tamoxifen resistance induced by light exposure at night in rodents. This study demonstrates that melatonin or melatonin-based ligands (e.g., melatonin-tamoxifen drug conjugates) may be novel BC therapies that are efficacious and free of side effects. To investigate this further, five melatonin-tamoxifen drug conjugates with different linker sizes were synthesized and screened for their anti-cancer actions in a variety of BC cells that included: MCF-7 (ER+), tamoxifen-resistant MCF-7 (TamR), MMC (HER2+), MDA-MB-231 (triple-negative), and BT-549 (triple-negative). Specifically, their actions against cell viability and migration and binding affinity to MT1 melatonin receptor (MT1Rs) and estrogen receptor 1 (ESR1) were assessed. The melatonin-tamoxifen drug conjugate linked with four (C4) or five (C5) carbons demonstrated the most favorable pharmacological characteristics with respect to potency and efficacy to inhibit BC cell viability and migration. C4 and C5 also exhibited unique binding profiles (affinity for ESR1 and MT1R) compared to the other conjugates. C4 and C5 were further assessed for their actions against tamoxifen-resistant (TamR) MCF-7 cells and patient-derived xenograft triple-negative BC cells (TU-BcX-4IC) as well as for potential mechanisms of action using selective MEK1/2, MEK5, and PI3K inhibitors. C4 and C5 inhibited TamR MCF-7 cells with equal potency and efficacy and both C4 and C5 inhibited TU-BcX-4IC cell viability. Even though both compounds demonstrated similar inhibitory actions against BC cell viability and migration, how this occurred, at a mechanistic level, was quite different between C4 and C5 in the cell lines. The underlying mechanisms of C4 and C5 in BC cell lines were context-specific and involved ERK1/2, ERK5, PI3 kinase, and NF-κB. They also exhibited unique pharmacokinetic profiles, where C4 had higher relative oral bioavailability than C5. These melatonin-tamoxifen drug conjugates show promise as novel anti-BC drugs.

Language

English

Additional Citations

1. M Hasan, MA Marzouk, S Adhikari, TD Wright, BP Miller, MD Matossian, S Elliott, M Wright, M Alzoubi, BM Collins-Burow, ME Burow, U Holzgrabe, DP Zlotos, RE Stratford, and PA Witt-Enderby (2019) Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs, Molecular Pharmacol, 96(2): 272-296; DOI:https://doi.org/10.1124/mol.119.116202

2. Hasan M, Leak RK, Stratford RE, Zlotos DP, Witt-Enderby PA. Drug conjugates—an emerging approach to treat breast cancer. Pharmacol Res Perspect. 2018;e00417. https://doi.org/10.1002/prp2.417

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