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

// Wohn-Jenn Leu 1, * , Sharada Prasanna Swain 2, * , She-Hung Chan 1 , Jui-Ling Hsu 1 , Shih-Ping Liu 3 , Mei-Ling Chan 1 , Chia-Chun Yu 1 , Lih-Ching Hsu 1 , Yen-Lin Chou 2 , Wei-Ling Chang 1 , Duen-Ren Hou 2 , Jih-Hwa Guh 1 1 School of Pharmacy, National Taiwan University, Taipei, Taiwan 2 Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan 3 Department of Urology, National Taiwan University Hospital, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Duen-Ren Hou, email: drhou@cc.ncu.edu.tw Jih-Hwa Guh, email: jhguh@ntu.edu.tw Keywords: triazole-base, non-immunosuppression, PI3K/Akt/mTOR signaling, Myc, autophagy Received: May 15, 2016      Accepted: October 14, 2016      Published: October 19, 2016 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.