No 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.

The data suggest that the ardisianone induces apoptosis in human prostate cancers through mitochondrial damage stress, leading to the inhibition of mTOR/p70S6K pathway, downregulation of Bcl-2 family members, degradation of survivin, and activation of caspase cascades. The data provide evidence supporting that ardisianone is a potential anticancer agent against HRPCs.

The data suggest that phentolamine is a potential anticancer agent. In contrast to a wide variety of microtubule disrupting agents, phentolamine induces microtubule assembly, leading to mitotic arrest of the cell cycle which "in turn" induces subsequent mitochondrial damage and activation of related apoptotic signaling pathways in CRPC cells. Furthermore, combination between phentolamine and paclitaxel induces a synergistic apoptotic cell death. Phentolamine has a simple chemical structure and is not a P-gp substrate. Optimization of phentolamine structure may also be a potential approach for further development.

Hormone-refractory metastatic prostate cancer (HRMPC), which is metastatic and resistant to hormone therapy, is an intractable problem in clinical treatment. Anthraquinone-based natural products and synthetic compounds have shown anticancer activity. However, cardiac toxicity is a major adverse reaction in these compounds. CC-36, a unique anthraquinone derivative, displayed higher antiproliferative activity in HRMPC than that in H9c2 cardiomyoblasts and normal prostate cells with the selectivity of five and twelve times, respectively. CC-36 caused G1 arrest of the cell cycle associated with an upregulation of p21 and downregulated levels of cyclin D1 and cyclin E expressions. Immunoprecipitation assay and Western blotting analysis showed that CC-36 triggered an increase of TSC1/TSC2 association and suppressed the phosphorylation of mammalian target of rapamycin (mTOR) (Ser2448) and p70 ribosomal protein S6 kinase (p70S6K) (Thr389), indicating the inhibition of both kinases' activities. CC-36 induced liver kinase B1 (LKB1) phosphorylation at Thr189, leading to LKB1 translocation from nucleus to cytosol for AMPKα phosphorylation (Thr172) and the kinase activation. The signaling pathway was validated using small interfering RNA (siRNA) technique with LKB1 knockdown. The combination treatment of MK2206 (a specific Akt inhibitor) with CC-36 showed a synergistic apoptosis in PC-3 cells indicating a potential combination strategy for LKB1 activators. Taken together, the data suggest that CC-36 displays anti-HRMPC activity through the activation of LKB1-AMPK pathway, leading to an inhibition of mTOR signaling and the induction of G1 arrest of the cell cycle. The combination use of Akt inhibitors with agents acting through LKB1-AMPK-mTOR pathway is a potential strategy for HRMPC treatment.