Inhibition of acetylpolyamine and spermine oxidases by the polyamine analogue chlorhexidine

""Acetylpolyamine and spermine oxidases are involved in the catabolism of polyamines. The discovery of selective. inhibitors of these enzymes represents an important tool for the development of novel anti-neoplastic drugs. Here, a. comparative study on acetylpolyamine and spermine oxidases inhibition by the polyamine analogue chlorhexidine. is reported. Chlorhexidine is an antiseptic diamide, commonly used as a bactericidal and bacteriostatic agent.. Docking simulations indicate that chlorhexidine binding to these enzymes is compatible with the stereochemical. properties of both acetylpolyamine oxidase and spermine oxidase active sites. In fact, chlorhexidine is predicted. to establish several polar and hydrophobic interactions with the active site residues of both enzymes, with binding. energy values ranging from −7.6 to −10.6 kcal\\\/mol. In agreement with this hypothesis, inhibition studies indicate that. chlorhexidine behaves as a strong competitive inhibitor of both enzymes, values of Ki being 0.10 μM and 0.55 μM for. acetylpolyamine oxidase and spermine oxidase, respectively."

Spermine metabolism and anticancer therapy

Abstract: The natural polyamines (PA), putrescine (PUT), spermidine (SPD) and spermine (SPM) are ubiquitous constituents of eukaryotic cells. The increase of PA in malignant and proliferating cells attracted the interest of scientists during last decades, addressing PA depletion as a new strategy to inhibit cell growth. Selective enzyme inhibitors were developed for decreasing PA metabolism and to act as chemotherapeutic anticancer agents. Indeed, the complexity of the PA homoeostasis overcomes the PA perturbation by a single enzyme to take effect therapeutically. Recently, an increasing interest has been posed on spermine-oxidase (SMO), the only catabolic enzyme able to specifically oxidise SPM. Interestingly, the absence of SPM is compatible with life, but its accumulation and degradation is lethal. Augmented SMO activity provokes an oxidative stress rendering cells prone to die, and appears to be important in the cell differentiation pathway. Extra-cellular SPM is cytotoxic, but its analogues are capable of inhibiting cell growth at low concentrations, most likely by intracellular SPM depletion. These pivotal roles seem to evoke the biological processes of stress response, wherein balance is mandatory to live or to die. Thus, altering SPM metabolism could allow a multi-tasking therapeutic strategy, addressed not only to inhibit PA metabolism. Several tetramines are presently in early phases (I and II) of clinical trials, and it will be a matter of a few more years to understand whether SPM-related therapeutic approaches would be of benefit for composite treatment protocols of cancer

Inflammation, Carcinogenesis and Neurodegeneration studies in transgenic animal models for polyamine research

Natural polyamines (PA) are cationic molecules affecting cell growth and proliferation. An association between increased polyamine biosynthesis and inflammation-induced carcinogenesis has been recognised. On the other hand, there are indications that inflammatory stimuli can up-regulate polyamine catabolism and that altered polyamine metabolism could affect pro- and anti-inflammatory cytokines. Since the polyamine content is strictly related to cell growth, a consistent number of evidences relate polyamine metabolism dysfunction with cancer. The increase of polyamine levels in malignant and proliferating cells attracted the interest of scientists during last decades, addressing polyamine depletion as a new strategy to inhibit carcinogenesis. Several studies suggest that PA also play an important role in neurodegeneration, but the mechanisms by which they participate in neuronal death are still unclear. Furthermore, the role of endogenous PA in normal brain functioning is yet to be elucidated. The consequences of an alteration of polyamine metabolism have also been approached in vivo with the use of transgenic animals overexpressing or devoid of some enzymes involved in polyamine metabolism. In the present work we review the experimental investigation carried out on inflammation, cancerogenesis and neurodegeneration using transgenic animals engineered as models for polyamine research