Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: The role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways

Please use this identifier to cite or link to this item: https://ir.lib.ncu.edu.tw/handle/987654321/101709

Title:	Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: The role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways
Authors:	侯敦仁;Leu, Wohn-Jenn;Swain, Sharada Prasanna;Chan, She-Hung;Hsu, Jui-Ling;Liu, Shih-Ping;Chan, Mei-Ling;Yu, Chia-Chun;Hsu, Lih-Ching;Chou, Yen-Lin;Chang, Wei-Ling;Hou, Duen-Ren;Guh, Jih-Hwa
Contributors:	理學院化學學系
Keywords:	Animals;Antineoplastic Agents - administration & dosage;Antineoplastic Agents - chemistry;Antineoplastic Agents - pharmacology;Cell Cycle - drug effects;Cell Line, Tumor;Cell Proliferation - drug effects;Cell Survival - drug effects;Fingolimod Hydrochloride - administration & dosage;Fingolimod Hydrochloride - pharmacology;Gene Expression Regulation, Neoplastic - drug effects;Humans;Male;Mice;Phosphatidylinositol 3-Kinases - metabolism;Prostatic Neoplasms, Castration-Resistant - drug therapy;Prostatic Neoplasms, Castration-Resistant - metabolism;Proto-Oncogene Proteins c-akt - metabolism;Proto-Oncogene Proteins c-myc - metabolism;Research Paper;Signal Transduction - drug effects;Small Molecule Libraries - administration & dosage;Small Molecule Libraries - chemistry;Small Molecule Libraries - pharmacology;TOR Serine-Threonine Kinases - metabolism;Triazoles - administration & dosage;Triazoles - chemistry;Triazoles - pharmacology;Xenograft Model Antitumor Assays
Date:	2016-01-01
Issue Date:	2026-04-21 14:41:26 (UTC+8)
Publisher:	United States: Impact Journals LLC
Abstract:	摘要： A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer. 其他題名： Oncotarget 出版者： United States: Impact Journals LLC 出版日期： 2016-11-22 出處： Oncotarget, 2016-11, Vol.7 (47), p.76995-77009 版權： Copyright: © 2016 Leu et al. 2016 識別號： ISSN: 1949-2553 識別號： EISSN: 1949-2553 識別號： DOI: 10.18632/oncotarget.12765 識別號： PMID: 27769069
Appears in Collections:	[Department of Chemistry] journal & Dissertation

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