PO.EN01.01 · 内分泌肿瘤

新型他莫昔芬-褪黑素药物偶联物对雌激素耐药肿瘤的抗肿瘤作用及其对SCID_BEIGE小鼠肿瘤和子宫表达的ESR1的作用

Anti-tumor actions of novel tamoxifen-melatonin drug conjugates on estrogen-resistant tumors and actions on tumor-and uterine-expressed ESR1 in SCID_BEIGE mice

编号 2296 展板 18 时间 4/20 09:00–12:00 区域 Section 34 主讲 Asef Faruk, B Pharm

分会场 Hormone Receptor Signaling and Therapeutic Targeting

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作者与单位 Authors & Affiliations

Asef Faruk¹, Sophie Dietrich², Yong Myoung¹, Afsana Jahan¹, Mohamed Marzouk³, Jane E. Cavanaugh¹, Simak Ali⁴, Matthew Burow², Darius Zlotos⁵, Paula Witt-Enderby¹

¹Pharmaceutical Sciences, Duquesne University School of Pharmacy, Pittsburgh, PA,²Section of Hematology & Medical Oncology, Tulane School of Medicine, New Orleans, LA,³Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany,⁴Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom,⁵Dept. of Pharmaceutical Chemistry, The German University in Cairo, Cairo, Egypt

摘要 Abstract

中文摘要

背景：他莫昔芬是FDA批准用于治疗ER+乳腺癌（BC）的选择性雌激素受体调节剂（SERM），但长期使用往往对子宫产生不良影响，并可导致他莫昔芬耐药。为抵消他莫昔芬介导的肿瘤耐药和促子宫作用，研发了具有不同CH2-间隔链长度的新型他莫昔芬-褪黑素药物偶联物C1-C5（美国专利号8,785,501 B2）。两种候选化合物C4和C5在MCF7、TNBC和他莫昔芬耐药的MCF7细胞中展示出抗乳腺癌作用（doi:10.1124/mol.119.116202）。方法：本研究的目的是使用SCID/BEIGE小鼠异种移植和蛋白质印迹分析，在体内评估C4和C5介导的对雌激素耐药乳腺癌的作用以及对子宫ESR1水平的影响。结果：使用CCK-8检测，评估C4和C5抑制ESR1突变型（MCF7-luc Y537S、MCF7-luc D538G、MCF7-E380Q）和亲本（MCF7-luc parental、MCF7-PE parental）细胞系增殖的效力和疗效，结果显示MCF7-lucD538G对C4（IC50=3.8μM；43%抑制）和C5（IC50=1.2μM；26%抑制）最为敏感。初步测试将MCF7-lucD538G或亲本细胞双侧植入SCID/BEIGE小鼠脂肪垫，给予或不给予额外雌激素，结果显示3周时肿瘤体积比亲本对照大60%至90%，提示雌激素非依赖性。将MCF7-luc D538G细胞（5×10^6）双侧植入SCID/BEIGE小鼠乳腺垫，在无雌激素条件下生长28天以形成肿瘤。随后开始使用C4或C5（1mg/kg/只/天，皮下）、DMSO（10% HP-beta-CD溶液）、他莫昔芬（植入5mg 60天缓释颗粒）、氟维司群（200mg/kg/周，皮下）治疗，持续28天。与DMSO和他莫昔芬处理的小鼠相比，C4和C5产生显著的肿瘤抑制；与氟维司群相比也观察到类似的肿瘤抑制作用（相对基线的变化百分比：DMSO=211%；他莫昔芬=169%；C4=134%；C5=95%；氟维司群=96%，n=5/组）。对肿瘤和子宫组织中ESR1水平的分析显示，他莫昔芬处理的小鼠中水平升高，而C4、C5和氟维司群处理的小鼠与对照相比无变化。在野生型MCF7细胞中进行ESR1稳定性检测，细胞分别暴露于载体（DMSO）以及各10μM的他莫昔芬、C4或C5达24小时，随后使用含放线菌酮（100μg/mL）的培养基进行撤药期（0、6、12、24小时）。与DMSO处理（T1/2=9.6h）和无处理细胞（T1/2=7.4h）相比，暴露于他莫昔芬（T1/2=13.2h）或C4（T1/2=12.6h）的细胞中观察到ESR1半衰期（T1/2）延长，而暴露于C5的MCF7细胞中观察到半衰期缩短（T1/2=5.1h）。结论：我们的研究结果表明，他莫昔芬-褪黑素药物偶联物可能是雌激素耐药以及潜在其他耐药癌症的一种可行乳腺癌治疗选择，同时提供子宫保护。

查看英文原文 English abstract

Background : Often, prolonged use of tamoxifen, an FDA approved SERM to treat ER+ breast cancer (BC), has untoward effects on the uterus and can lead to tamoxifen resistance. Novel tamoxifen-melatonin drug conjugates, C1-C5, with varying CH2- spacer lengths were developed (US Patent No. 8,785,501 B2) to offset tamoxifen-mediated tumor resistance and uterotropic actions. Two candidate compounds, C4 and C5, demonstrated anti-BC actions in MCF7, TNBC, and tamoxifen-resistant MCF7 cells (doi:10.1124/mol.119.116202). Methods: The goal of this study was to evaluate C4- and C5-mediated actions on estrogen resistant BC in vivo and ESR1 levels in the uterus in vivo using SCID/BEIGE mouse xenografts and western blot analyses. Results: Using CCK-8 assays, C4- and C5-mediated potency and efficacy to inhibit proliferation of ESR1 mutant (MCF7-luc Y537S, MCF7-luc D538G, MCF7-E380Q) and parental (MCF7-luc parental, MCF7-PE parental) lines revealed MCF7-lucD538G to be most sensitive to C4 (IC 50 = 3.8μM; 43% inhibition) and C5 (IC 50 =1.2μM; 26% inhibition). Preliminary testing using MCF7-lucD538G or parental cells bilaterally implanted into fat pads of SCID/BEIGE mice given additional estrogen or not demonstrated 60% to 90% greater tumor volumes compared to parental controls by 3 weeks, suggesting estrogen-independence. MCF7-luc D538G cells (5x10 6 ), were bilaterally implanted in the mammary pads of SCID/BEIGE mice and grown for 28 days in the absence of estrogen to allow for tumor formation. Next, treatments with C4 or C5 (1mg/kg/mouse/day, sc,), DMSO (10% in HP-beta-CD), tamoxifen (5mg 60-day release pellet implanted), fulvestrant (200mg/kg/week, sc) began and continued for 28 days. Significant tumor inhibition occurred with C4 and C5 vs DMSO- and tamoxifen-treated mice; and similar tumor-inhibiting effects were observed when compared to fulvestrant (% change from baseline: DMSO=211%; tamoxifen=169%; C4=134%; C5=95%; fulvestrant=96%, n=5/group). Analysis of ESR1 levels in tumor and uterine tissue demonstrated increases in levels in tamoxifen-treated mice and no changes in C4-, C5- and fulvestrant-treated mice vs control. ESR1 stability assays were conducted in wildtype MCF7 cells exposed to vehicle (DMSO), and 10μM each of tamoxifen, C4 or C5 for 24h, followed by a withdrawal period (0, 6, 12, 24h) using media containing cycloheximide (100μg/mL). Increases in the half-life (T 1/2 ) of ESR1 were observed in cells exposed to tamoxifen (T 1/2 =13.2h) or C4 (T 1/2 =12.6h) while decreases were observed in MCF7 cells exposed to C5 (T 1/2 =5.1h) compared to DMSO-treated (T 1/2 =9.6h) and no treatment cells ((T 1/2 =7.4h). Conclusion: Our findings indicate that tamoxifen-melatonin drug conjugates may be a viable BC treatment option for estrogen-resistant and potentially other resistant cancers while offering uterine protection.

利益披露 Disclosure

A. Faruk, None.. S. Dietrich, None.. Y. Myoung, None.. A. Jahan, None.. M. Marzouk, None.. J. E. Cavanaugh, None.. S. Ali, None.. M. Burow, None.. D. Zlotos, None.. P. Witt-Enderby, None.

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