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
Journal
Oncotarget
Journal Volume
7
Journal Issue
47
Pages
76995-77009
Date Issued
2016
Author(s)
Leu W.-J.
Swain S.P.
Chan S.-H.
Hsu J.-L.
Chan M.-L.
Yu C.-C.
Chou Y.-L.
Chang W.-L.
Hou D.-R.
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 blockmediated 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, downregulation 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.
SDGs
Other Subjects
1,3 dihydroxy 2 [(1 octadecyl 1h 1,2,3 triazol 4 yl)methyl]propan 2 aminium chloride; cyclin D1; fingolimod; initiation factor 4E binding protein 1; mammalian target of rapamycin; Myc protein; phosphatidylinositol 3 kinase; protein kinase B; S6 kinase; sphingosine 1 phosphate receptor; triazole derivative; unclassified drug; antineoplastic agent; fingolimod; MTOR protein, human; Myc protein; MYC protein, human; phosphatidylinositol 3 kinase; protein kinase B; target of rapamycin kinase; triazole derivative; animal experiment; animal model; animal tissue; antineoplastic activity; antiproliferative activity; apoptosis; Article; autophagy; B lymphocyte; cancer inhibition; castration resistant prostate cancer; cell cycle regulation; cell proliferation; cell survival; controlled study; drug cytotoxicity; drug efficacy; drug selectivity; drug synthesis; G1 phase cell cycle checkpoint; human; human cell; human tissue; IC50; immunomodulation; in vitro study; in vivo study; lymphocyte homing; male; mitochondrial membrane potential; mouse; nonhuman; peripheral lymphocyte; prostate cancer cell line; protein expression; receptor down regulation; signal transduction; structure activity relation; translation regulation; tumor xenograft; administration and dosage; animal; castration resistant prostate cancer; cell cycle; chemistry; drug effects; drug screening; gene expression regulation; metabolism; molecular library; pharmacology; signal transduction; tumor cell line; Animals; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Fingolimod Hydrochloride; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Signal Transduction; Small Molecule Libraries; TOR Serine-Threonine Kinases; Triazoles; Xenograft Model Antitumor Assays
Publisher
Impact Journals LLC
Type
journal article