Tarek K Motawi1, Hebatallah A Darwish2, Iman Diab3, Maged W Helmy4, Mohamed H Noureldin5. 1. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: tarek.motawi@pharma.cu.edu.eg. 2. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Egypt; Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University, Cairo, Egypt. Electronic address: hebatallah.darwish@pharma.cu.edu.eg. 3. Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Electronic address: diab@alexmed.edu.eg. 4. Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, El-Bahira, Egypt. Electronic address: maged.helmy@pharm.dmu.edu.eg. 5. Department of Pharmacology and Biochemistry, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, Alexandria, Egypt. Electronic address: mohamed.noureldin@aast.edu.
Abstract
AIMS: Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-β appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERβ expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERβ1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERβ1 agonist, in prostate cancer cell line PC-3. MAIN METHODS: Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERβ1 expression, protein levels of active caspase-3, cyclin D1, β-catenin and VEGF. KEY FINDINGS: Treatment with these drugs exhibited an increase in ERβ1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and β-catenin levels was achieved as compared to the vehicle control group (p < 0.05). Interestingly, the triple combination regimen led to the most prominent anti-tumor responses in terms of increased apoptosis, reduced proliferation as well as angiogenesis. SIGNIFICANCE: The results support the notion that ERβ1 acts as a tumor suppressor protein and suggest that sequential ERβ1 expression and activation can offer significant anti-tumor responses. The study highlights that the strategy of merging epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer.
AIMS: Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-β appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERβ expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERβ1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERβ1 agonist, in prostate cancer cell line PC-3. MAIN METHODS: Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERβ1 expression, protein levels of active caspase-3, cyclin D1, β-catenin and VEGF. KEY FINDINGS: Treatment with these drugs exhibited an increase in ERβ1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and β-catenin levels was achieved as compared to the vehicle control group (p < 0.05). Interestingly, the triple combination regimen led to the most prominent anti-tumor responses in terms of increased apoptosis, reduced proliferation as well as angiogenesis. SIGNIFICANCE: The results support the notion that ERβ1 acts as a tumor suppressor protein and suggest that sequential ERβ1 expression and activation can offer significant anti-tumor responses. The study highlights that the strategy of merging epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer.
Authors: Benjamin M Johnson; Faisal F Y Radwan; Azim Hossain; Bently P Doonan; Jessica D Hathaway-Schrader; Jason M God; Christina V Voelkel-Johnson; Narendra L Banik; Sakamuri V Reddy; Azizul Haque Journal: J Cell Biochem Date: 2018-10-30 Impact factor: 4.429
Authors: Jasmina Makarević; Jochen Rutz; Eva Juengel; Sebastian Maxeiner; Jens Mani; Stefan Vallo; Igor Tsaur; Frederik Roos; Felix K-H Chun; Roman A Blaheta Journal: Cells Date: 2018-09-01 Impact factor: 6.600