B S Yurekli1, B Karaca2, A Kisim3, E Bozkurt3, H Atmaca3, S Cetinkalp4, G Ozgen4, C Yilmaz4, S Uzunoglu3, R Uslu2, F Saygili4. 1. Division of Endocrinology and Metabolism, Ege University School of Medicine, 35100, Izmir, Turkey. bsareryurekli@yahoo.com. 2. Division Medical Oncology, Tulay Aktas Oncology Hospital, Ege University School of Medicine, 35100, Izmir, Turkey. 3. Section of Molecular Biology, Department of Biology, Faculty of Science and Letters, Celal Bayar University, 45140, Muradiye/Manisa, Turkey. 4. Division of Endocrinology and Metabolism, Ege University School of Medicine, 35100, Izmir, Turkey.
Abstract
PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS: Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. RESULTS: AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION: AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells.
PURPOSE:Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS:Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. RESULTS:AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION:AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells.
Authors: Gary D Hammer; J Blake Tyrrell; Kathleen R Lamborn; Carol B Applebury; Elizabeth T Hannegan; Scott Bell; Riva Rahl; Amy Lu; Charles B Wilson Journal: J Clin Endocrinol Metab Date: 2004-12 Impact factor: 5.958
Authors: Rosario Pivonello; Maria Cristina De Martino; Monica De Leo; Gaetano Lombardi; Annamaria Colao Journal: Endocrinol Metab Clin North Am Date: 2008-03 Impact factor: 4.741
Authors: Michael A Chattergoon; Karuppiah Muthumani; Yutaka Tamura; Mathura Ramanathan; Jason P Shames; Vera Saulino; Tara M Robinson; Luis J Montaner; David B Weiner Journal: Mol Ther Date: 2007-12-18 Impact factor: 11.454