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Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation.
Dos Santos, Diandra Zipinotti; Elbaz, Mohamad; Branchard, Emily; Schormann, Wiebke; Brown, Carla E; Meek, Autumn R; Njar, Vincent C O; Hamilton, Robert J; Reed, Mark A; Andrews, David W; Penn, Linda Z.
Afiliación
  • Dos Santos DZ; Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
  • Elbaz M; Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Ain Helwan, Helwan, Cairo, Egypt.
  • Branchard E; Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
  • Schormann W; Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
  • Brown CE; Krembil Research Institute, 60 Leonard Ave, Toronto, ON M5T 0S8, Canada.
  • Meek AR; Krembil Research Institute, 60 Leonard Ave, Toronto, ON M5T 0S8, Canada.
  • Njar VCO; Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Compreh
  • Hamilton RJ; Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Reed MA; Krembil Research Institute, 60 Leonard Ave, Toronto, ON M5T 0S8, Canada; Department of Pharmacology and Toxicology, Medical Sciences Building,1 King's College Circle, University of Toronto, M5S 1A8, Canada; Department of Chemistry, Lash Miller Building, 80 St. George Street, University of Toronto, O
  • Andrews DW; Biological Sciences, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Biochemistry, University of Toronto, 27 King's College Cir, Toronto, ON M5S 1A1, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
  • Penn LZ; Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada. Electronic address: Linda.Penn@uhnresearch.ca.
Biomed Pharmacother ; 177: 116934, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38889639
ABSTRACT
There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Proteína 2 de Unión a Elementos Reguladores de Esteroles Límite: Animals / Humans / Male Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Proteína 2 de Unión a Elementos Reguladores de Esteroles Límite: Animals / Humans / Male Idioma: En Revista: Biomed Pharmacother Año: 2024 Tipo del documento: Article Pais de publicación: Francia