新型褪黑素-他莫昔芬药物偶联物作为乳腺癌药物的药理学、机制和药代动力学评估。
Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs.
机构信息
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.).
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.)
出版信息
Mol Pharmacol. 2019 Aug;96(2):272-296. doi: 10.1124/mol.119.116202. Epub 2019 Jun 20.
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 = 4-8 M) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC = 80-211 M) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC = 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 B. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.
他莫昔芬用于预防和治疗雌激素受体阳性（ER+）乳腺癌（BC）；然而，其长期使用会增加子宫癌风险，并诱导他莫昔芬耐药。新型褪黑素-他莫昔芬药物偶联物可能对治疗 BC 有希望，并可能有助于抵消由于褪黑素的存在而单独使用他莫昔芬的不良反应。我们合成并筛选了五种药物偶联物（C2、C4、C5、C9 和 C15 连接），以研究它们对 BC 细胞（MCF-7、他莫昔芬耐药 MCF-7、鼠乳腺癌、MDA-MB-231 和 BT-549）活力、迁移以及与褪黑素受体 1（MT1R）和雌激素受体 1（ESR1）结合亲和力的影响。C4 和 C5 在结合谱（对 ESR1 和 MT1R 的亲和力）及其抑制四种表型不同的侵袭性乳腺导管 BC 细胞系中 BC 细胞活力和迁移的效力/功效方面表现出最有利的药理学特征。C4 和 C5 进一步用于评估它们对他莫昔芬耐药 MCF-7 细胞和源自患者的异种移植三阴性 BC 细胞系（TU-BcX-4IC）的作用，并使用选择性丝裂原活化蛋白激酶激酶 MEK1/2、MEK5 和磷酸肌醇 3-激酶（PI3K）抑制剂研究它们的作用机制。C4 和 C5 以相同的效力（IC=4-8 μM）和功效（对活力和迁移的抑制约为 90%）抑制他莫昔芬耐药 MCF-7 细胞，但在 TU-BcX-4IC 细胞中对迁移的抑制作用更强（IC=80-211 μM）和功效（对迁移的抑制约为 140%，对活力的抑制约为 80%）。观察到独特的药代动力学特征，C4 的生物利用度大于 C5。对 C4 和 C5 的进一步评估表明，它们在每个 BC 细胞中创建了新的药效团，这是特定于上下文的，涉及 MEK1/2/pERK1/2、MEK5/pERK5、PI3K 和核因子 B。这些褪黑素-他莫昔芬药物偶联物作为新型抗癌药物具有前景，需要进一步的临床前和临床评估。
Zotero 插件