Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs: Pharmacological Evaluation in Phenotypically Diverse Breast Cancer Models and Pharmacokinetic Assessment in Liver Microsome and Female Mouse Models

<p>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.</p>

Name thesis:degree_name

PhD

Level thesis:degree_level

Immediate Access

Discipline thesis:degree_discipline

Pharmacology

Year dc:date.available

2020

Author dc:creator

• Hasan, Mahmud

Contributors dc:contributor

• Paula A. Witt-Enderby
• David A. Johnson
• Jane E. Cavanaugh
• Lauren A. O’Donnell
• Robert E. Stratford

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

Language dc:language

English

Repository record dc:identifier

https://dsc.duq.edu/etd/1935

OAI identifier oai:identifier

oai:dsc.duq.edu:etd-2946