TY - JOUR T1 - Title: Pharmacological, mechanistic and pharmacokinetic assessment of novel melatonin-tamoxifen drug conjugates as breast cancer drugs JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.116202 SP - mol.119.116202 AU - Mahmud Hasan AU - Mohamed Akmal Marzouk AU - Saugat Adhikari AU - Thomas D Wright AU - Benton P Miller AU - Margarite D Matossian AU - Steven Elliott AU - Maryl K Wright AU - Madlin S. Alzoubi AU - Bridgette M Collins-Burow AU - Matthew E Burow AU - Ulrike Holzgrabe AU - Darius P Zlotos AU - Robert E Stratford AU - Paula A Witt-Enderby Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/06/19/mol.119.116202.abstract N2 - 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, TamR MCF-7, MMC, MDA-MB-231, and BT-549) viability, migration and binding affinity to the MT1 melatonin receptor (MT1Rs) 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 4 phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant (TamR) MCF-7 cells and a patient-derived xenograft triple negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective MEK1/2, MEK5 and PI3K inhibitors. C4 and C5 inhibited TamR MCF-7 cells with equal potency (IC50= 4-8 μM) and efficacy (~90% inhibition of viability and migration) but demonstrated increased potency (IC50 = 80-211 μM) and efficacy (~140% inhibition) to inhibit migration versus cell viability (IC50 = 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 demonstrate that they create novel pharmacophores within each BC cell that is context-specific and involves MEK1/2/pERK1/2, MEK5/pERK5 and PI3 kinase and NF-κB. These melatonin-tamoxifen drug conjugates show promise as novel anti-cancer drugs and further pre-clinical and clinical evaluation is warranted.SIGNIFICANCE STATEMENT Novel melatonin-tamoxifen drug conjugates linked with 4 (C4) or 5 (C5) carbons demonstrate anti-cancer actions against myriad breast cancer lines including: ER+ (MCF-7), HER2+ (MMC), TamR (MCF-7 tamoxifen resistant) and in TNBC cells (MDA-MB-231, BT549) and PDX-TNBC (TU-BcX-4IC) superior to that of melatonin alone, tamoxifen alone or melatonin plus tamoxifen (unlinked). C4 and C5 demonstrate unique pharmacokinetic profiles with C4 having greater bioavailability than C5. C4 and C5 demonstrate that they create novel pharmacophores within each BC cell that is context-specific and involves MEK1/2/pERK1/2, MEK5/pERK5 and PI3 kinase and NF-κB. ER -