甲苯咪唑治疗和维持卵巢癌的潜力和机制,Gynecologic Oncology

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甲苯咪唑治疗和维持卵巢癌的潜力和机制
Gynecologic Oncology ( IF 4.5 ) Pub Date : 2020-10-31 , DOI: 10.1016/j.ygyno.2020.10.010
Suganthapriya Elayapillai ₁ , Satishkumar Ramraj ₂ , Doris Mangiaracina Benbrook ₃ , Magdalena Bieniasz ₄ , Lin Wang ₄ , Gopal Pathuri ₅ , Zitha Redempta Isingizwe ₆ , Amy L Kennedy ₇ , Yan D Zhao ₈ , Stanley Lightfoot ₉ , Lauri A Hunsucker ₁ , Camille C Gunderson ₂

Affiliation

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Oklahoma City 73117, OK, USA; Department of Pathology, College of Medicine, Oklahoma City 73104, OK, USA.
Patient-Derived Xenograft and Preclinical Therapeutics Core facility, Aging and Metabolism Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Oklahoma City 73117, OK, USA.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Oklahoma City 73117, OK, USA.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Department of Pathology, College of Medicine, Oklahoma City 73104, OK, USA.
Biostatistics & Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA; Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA.

客观的

基于社交媒体和非官方的抗癌活性报道，甲苯咪唑和其他抗寄生虫药物被非处方药使用。本研究的目的是对甲苯咪唑在细胞培养和卵巢癌体内模型中的治疗效果进行对照评估。大多数卵巢癌存在 p53 无效或错义突变，因此评估了 p53 突变和突变 p53 再激活剂 PRIMA-1 ^MET (APR246) 对甲苯咪唑活性的影响。

方法

甲苯咪唑在耐顺铂的高级浆液性 3C 期卵巢癌患者衍生的异种移植物 (PDX) 模型中进行了评估：PDX-0003（p53 无效）和 PDX-0030（p53 阳性），以及卵巢癌细胞系：MES-OV（p53 R282W)、ES2 (p53 S241F)、A2780 (p53 野生型)、SKOV3 亲本 (p53 null) 和同基因亚系、SKOV3 R273H p53 和 SKOV3 R248W p53。使用等效线图、克隆形成测定和蛋白质印迹在细胞培养物中评估药物协同作用和机制。在 MES-OV 原位模型中研究了肿瘤形成的预防。

结果

甲苯咪唑在纳摩尔浓度下抑制卵巢癌细胞培养物的生长，在剂量高达 50 mg/kg 时抑制 PDX，并在 50 mg/kg 时减少原位肿瘤的形成。甲苯咪唑的作用机制与 p53 非依赖性诱导 p21 和小管解聚有关。PRIMA-1 ^MET还抑制肿瘤形成，并与细胞培养物中的甲苯咪唑协同作用，通过不依赖 p53 和小管不稳定的机制抑制生长并诱导内在细胞凋亡。

结论

这项工作证明了重新利用甲苯达唑的治疗潜力，并支持甲苯达唑用于卵巢癌治疗和维持的临床开发。

"点击查看英文标题和摘要"

Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer

Objective

Mebendazole and other anti-parasitic drugs are being used off-prescription based on social media and unofficial accounts of their anti-cancer activity. The purpose of this study was to conduct a controlled evaluation of mebendazole's therapeutic efficacy in cell culture and in vivo models of ovarian cancer. The majority of ovarian cancers harbor p53 null or missense mutations, therefore the effects of p53 mutations and a mutant p53 reactivator, PRIMA-1^MET (APR246) on mebendazole activity were evaluated.

Methods

Mebendazole was evaluated in cisplatin-resistant high grade serous stage 3C ovarian cancer patient derived xenograft (PDX) models: PDX-0003 (p53 null) and PDX-0030 (p53 positive), and on ovarian cancer cell lines: MES-OV (p53 R282W), ES2 (p53 S241F), A2780 (p53 wild type), SKOV3 parental (p53 null) and isogenic sublines, SKOV3 R273H p53 and SKOV3 R248W p53. Drug synergy and mechanisms were evaluated in cell cultures using isobolograms, clonogenic assays and western blots. Prevention of tumor establishment was studied in a MES-OV orthotopic model.

Results

Mebendazole inhibited growth of ovarian cancer cell cultures at nanomolar concentrations and PDXs at doses up to 50 mg/kg, and reduced orthotopic tumor establishment at 50 mg/kg. The mechanism of mebendazole was associated with p53-independent induction of p21 and tubule depolymerization. PRIMA-1^MET also inhibited tumor establishment and worked synergistically with mebendazole in cell culture to inhibit growth and induce intrinsic apoptosis through a p53- and tubule destabilization-independent mechanism.

Conclusion

This work demonstrates the therapeutic potential of repurposing mebendazole and supports clinical development of mebendazole for ovarian cancer therapy and maintenance.

更新日期：2020-12-30

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