The Emerging Clinical Role of Spermine in Prostate Cancer

Spermine, a member of polyamines, exists in all organisms and is essential for normal cell growth and function. It is highly expressed in the prostate compared with other organs and is detectable in urine, tissue, expressed prostatic secretions, and erythrocyte. A significant reduction of spermine level was observed in prostate cancer (PCa) tissue compared with benign prostate tissue, and the level of urinary spermine was also significantly lower in men with PCa. Decreased spermine level may be used as an indicator of malignant phenotype transformation from normal to malignant tissue in prostate. Studies targeting polyamines and key rate-limiting enzymes associated with spermine metabolism as a tool for PCa therapy and chemoprevention have been conducted with various polyamine biosynthesis inhibitors and polyamine analogues. The mechanism between spermine and PCa development are possibly related to the regulation of polyamine metabolism, cancer-driving pathways, oxidative stress, anticancer immunosurveillance, and apoptosis regulation. Although the specific mechanism of spermine in PCa development is still unclear, ongoing research in spermine metabolism and its association with PCa pathophysiology opens up new opportunities in the diagnostic and therapeutic roles of spermine in PCa management.

Controlling of N-alkylpolyamine analogue metabolism by selective deuteration

Replacing protium with deuterium is an efficient method to modulate drug metabolism. N-alkylated polyamine analogues are polyamine antimetabolites with proven anticancer efficacy. We have characterized earlier the preferred metabolic routes of N1,N12-diethylspermine (DESpm), N1-benzyl-N12-ethylspermine (BnEtSpm) and N1,N12-dibenzylspermine (DBSpm) by human recombinant spermine oxidase (SMOX) and acetylpolyamine oxidase (APAO). Here, we studied the above analogues, their variably deuterated counterparts and their metabolites as substrates and inhibitors of APAO, SMOX, semicarbazide-sensitive amine oxidase (SSAO), diamine oxidase (DAO) and monoamine oxidases. We found that targeted deuteration efficiently redirected the preferable cleavage site and suppressed reaction rate by APAO and SMOX in vitro. We found a three- to six-fold decline in Vmax with moderate variable effect on Km when deuterium was located at the preferred hydrogen abstraction site of the analogue. We also found some of the metabolites to be potent inhibitors of DAO and SSAO. Surprisingly, analogue deuteration did not markedly alter the anti-proliferative efficacy of the drugs in DU145 prostate cancer cells, while in mouse embryonic fibroblasts, which had higher basal APAO and SMOX activities, moderate effect was observed. Interestingly, the anti-proliferative efficacy of the analogues did not correlate with their ability to suppress polyamine biosynthetic enzymes, induce spermidine/spermine-N1-acetyltransferase or deplete intracellular polyamine levels, but correlated with their ability to induce SMOX. Our data show that selective deuteration of N-alkyl polyamine analogues enables metabolic switching, offering the means for selective generation of bioactive metabolites inhibiting, e.g. SSAO and DAO, thus setting a novel basis for in vivo studies of this class of analogues.

Identification of Deregulated Signaling Pathways in Jurkat Cells in Response to a Novel Acylspermidine Analogue-N4-Erucoyl Spermidine

Natural polyamines such as putrescine, spermidine, and spermine are crucial in the cell proliferation and maintenance in all the eukaryotes. However, the requirement of polyamines in tumor cells is stepped up to maintain tumorigenicity. Many synthetic polyamine analogues have been designed recently to target the polyamine metabolism in tumors to induce apoptosis. N4-Erucoyl spermidine (designed as N4-Eru), a novel acylspermidine derivative, has been shown to exert selective inhibitory effects on both hematological and solid tumors, but its mechanisms of action are unknown. In this study, RNA sequencing was performed to investigate the anticancer mechanisms of N4-Eru-treated T-cell acute lymphoblastic leukemia (ALL) cell line (Jurkat cells), and gene expression was examined through different tools. We could show that many key oncogenes including NDRG1, CACNA1G, TGFBR2, NOTCH1,2,3, UHRF1, DNMT1,3, HDAC1,3, KDM3A, KDM4B, KDM4C, FOS, and SATB1 were downregulated, whereas several tumor suppressor genes such as CDKN2AIPNL, KISS1, DDIT3, TP53I13, PPARG, FOXP1 were upregulated. Data obtained through RNA-Seq further showed that N4-Eru inhibited the NOTCH/Wnt/JAK-STAT axis. This study also indicated that N4-Eru-induced apoptosis could involve several key signaling pathways in cancer. Altogether, our results suggest that N4-Eru is a promising drug to treat ALL.

Inhibition of FAD-dependent lysine-specific demethylases by chiral polyamine analogues

Polyamine-based inhibitors of lysine-specific demethylases 1 and 2 (LSD1 and LSD2) have been developed using solid-phase synthesis.