Suganthapriya Elayapillai1, Satishkumar Ramraj2, Doris Mangiaracina Benbrook3, Magdalena Bieniasz4, Lin Wang4, Gopal Pathuri5, Zitha Redempta Isingizwe6, Amy L Kennedy7, Yan D Zhao8, Stanley Lightfoot9, Lauri A Hunsucker1, Camille C Gunderson10. 1. Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA. 2. 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. 3. 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. 4. Patient-Derived Xenograft and Preclinical Therapeutics Core facility, Aging and Metabolism Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. 5. 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. 6. 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. 7. 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. 8. Biostatistics & Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City 73104, OK, USA. 9. 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. 10. 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. Electronic address: Camille-Gunderson@ouhsc.edu.
Abstract
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-1MET (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-1MET 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.
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-1MET (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-1MET 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.
Authors: Eunhye Oh; Yoon-Jae Kim; Hyunsook An; Daeil Sung; Tae-Min Cho; Lee Farrand; Seojin Jang; Jae Hong Seo; Ji Young Kim Journal: Int J Cancer Date: 2018-07-10 Impact factor: 7.396