Mechanism of cell death induced by spermine and amine oxidase in mouse melanoma cells

Abstract

Abstract. Polyamines such as spermine, spermidine and putrescine are necessary for cell proliferation and are detected at higher concentrations in most tumor tissues, compared to normal tissues. The amine oxidase enzymes can generate cytotoxic products such as hydrogen peroxide and aldehydes from these polyamines. This study investigates the mechanisms of cell death in B16-F0 mouse melanoma tumor cells exposed to bovine serum amine oxidase and exogenous spermine. The bovine serum amine oxidase/spermine enzymatic system induced inhibition of cell proliferation in B16-F0 melanoma cells and cell death by both apoptotic and necrotic processes. Bovine serum amine oxidase or spermine, alone, did not induce cytotoxicity or cell death by apoptosis, indicating that the enzymatic reaction products were responsible. Catalase and NAD-dependent aldehyde dehydrogenase, inhibitors of hydrogen peroxide and aldehydes, respectively, decreased cell death by apoptosis and necrosis. This further confirms that the cytotoxic products are responsible for causing cell death. Use of inhibitors of different caspases showed that melanoma cells were sensitive to processes involving caspase-3 and -9, but were insensitive to caspase-6. Bovine serum amine oxidase in the presence of spermine could be useful as a promising new tool for anticancer treatment by the selective generation of toxic compounds from polyamines in tumors.

Optimizing the design and in vitro evaluation of bioreactive glucose oxidase-microspheres for enhanced cytotoxicity against multidrug resistant breast cancer cells

“…It has been reported that MDR cells contain more specific lipids than WT cells, such as sphingolipids, phosphatidylinositol, cholesterol, and cholesterol esters, and thus degree of lipid peroxidation has been suggested as a surrogate for the influence of ROS on MDR cells [41,[43][44][45]. It has also been confirmed that MDR cells are more sensitive to H 2 O 2 and aldehyde, the products of lipid peroxidation, than their WT counterpart [14,17,18]. Recently acrolein, a highly reactive aldehyde produced by lipid peroxidation, has been found to cause apoptotic cell death mediated by endoplasmic reticulum stress [46].…”

“…Reactive oxygen species (ROS)-generating enzymes have also been explored to overcome MDR in cancer cells [12][13][14][15][16][17][18] based on the knowledge that cancer cells express higher ROS levels than normal cells and MDR cells are more susceptible to excess exogenous ROS than non-resistant cells [19][20][21][22][23][24][25][26][27]. Indeed, ROS-generated by the enzyme bovine serum amine oxidase (BSAO) caused higher toxicity in Pgp-expressing MDR cells than wild-type cells [12][13][14] and MDR cells were more sensitive to the enzymatic reaction products H 2 O 2 and aldehyde than their wild-type counterpart cells [17,18]. Moreover, excess ROS was found to down regulate Pgp in MDR cells contributing to the reversal of the MDR phenotype [16,[27][28][29][30].…”

“…Various approaches have been investigated to overcome membrane transporter-mediated MDR, including use of inhibitors of efflux transporters, chemosensitizers, gene therapy, silencing agents, and nanoparticulate drug carriers [2][3][4][5][6][7][8][9][10][11]. Reactive oxygen species (ROS)-generating enzymes have also been explored to overcome MDR in cancer cells [12][13][14][15][16][17][18] based on the knowledge that cancer cells express higher ROS levels than normal cells and MDR cells are more susceptible to excess exogenous ROS than non-resistant cells [19][20][21][22][23][24][25][26][27]. Indeed, ROS-generated by the enzyme bovine serum amine oxidase (BSAO) caused higher toxicity in Pgp-expressing MDR cells than wild-type cells [12][13][14] and MDR cells were more sensitive to the enzymatic reaction products H 2 O 2 and aldehyde than their wild-type counterpart cells [17,18].…”

Modulation of Adhesion Proteins Integrin β1 and FAK, and Cytoskeletal Protein Actin by Spermine in MCF-7 Cells

“…Among polyamines, spm was most effective in inhibiting cancer cell growth. The cytotoxicity of spm has been suggested by the production of H2O2 and aldehyde(s) from spm in the presence of amine oxidase [1,2].…”

“…Among polyamines, spm was most effective in inhibiting cancer cell growth. The cytotoxicity of spm has been suggested by the production of H2O2 and aldehyde(s) from spm in the presence of amine oxidase [1,2].Polyamines are also essential for the normal attachment of cells to the extracellular matrix (ECM), which explains at least some of the reliance of cell migration and the organization of the cytoskeleton on normal polyamine levels [22]. The migration of cells depends on their ability to make and break attachments to the ECM.…”