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.
abstract: 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.
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Wohn-Jenn
authors: WJ
authors: Leu
authors: Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan.
authors: Sharada Prasanna
authors: ShP
authors: Swain
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: She-Hung
authors: SH
authors: Chan
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Jui-Ling
authors: JL
authors: Hsu
authors: Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
authors: Shih-Ping
authors: SP
authors: Liu
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Mei-Ling
authors: ML
authors: Chan
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Chia-Chun
authors: CC
authors: Yu
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Lih-Ching
authors: LC
authors: Hsu
authors: Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan.
authors: Yen-Lin
authors: YL
authors: Chou
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Wei-Ling
authors: WL
authors: Chang
authors: Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan.
authors: Duen-Ren
authors: DR
authors: Hou
authors: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors: Jih-Hwa
authors: JH
authors: Guh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000068876:Fingolimod Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D054852:Small Molecule Libraries; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C489427:MYC protein, human; C546842:MTOR protein, human
keywords: Myc; PI3K/Akt/mTOR signaling; autophagy; non-immunosuppression; triazole-base