Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

Abstract

Polyamine analogue treatment results in growth inhibition and sometimes in cell death. Therefore, polyamine analogues are considered in the treatment of cancer; however, the cellular properties that govern sensitivity are not known. The objective of this study was to elucidate molecular mechanisms behind apoptosis induced by the polyamine analogue N, N-diethylnorspermine (DENSPM). Four different breast cancer cell lines were treated with DENSPM. Cell death was evaluated with flow cytometry and a caspase 3 assay. The levels of a number of proapoptotic and antiapoptotic proteins in subcellular compartments were evaluated with western blot. In the most sensitive cell line, DENSPM treatment induced the release of cytochrome c from mitochondria, resulting in activation of caspase 3 but without decreasing the mitochondrial transmembrane potential. However, in the three other cell lines DENSPM treatment did not induce extensive cell death. This is partly explained by the high levels of antiapoptotic proteins Bcl-2 and Bad and low levels of proapoptotic proteins Bax and procaspase 3 in these three cell lines. The results are also partly explained by the degree of activation of the catabolic enzyme spermidine/spermine-N-acetyltransferase and polyamine pool reduction achieved by DENSPM treatment. Our results show that the protein profile of proapoptotic and antiapoptotic proteins may contribute to the outcome to treatment with the polyamine analogue DENSPM. The results also indicate that it should be possible to find molecular markers for sensitivity to DENSPM that could be used in the clinic to predict sensitivity to a polyamine analogue.

RETRACTED ARTICLE: NPC-16, a novel naphthalimide–polyamine conjugate, induced apoptosis and autophagy in human hepatoma HepG2 cells and Bel-7402 cells

“…This effect is similar to that of ANTMHspd [16] but not that of DENspm [24], for DENspm only triggered the release of cytochrome c from mitochondria without decreasing the MMP of mitochondria. Previous studies have shown that Bcl-2 family proteins were usually involved in polyamine conjugate induced mitochondria apoptotic signal pathway [25,26]. Accordingly, we turned our attention to Bad and Bcl-2, two pivotal pro-apoptotic and anti-apoptotic Bcl-2 family members [27].…”

Cytotoxic Sesquiterpene Lactones from Kauna lasiophthalma Griseb

“…The L56Br-C1, MCF-7, SK-BR-3, and HCC1937 cells were cultured as described by Holst et al [33]. JIMT-1 cells were cultured in DMEM/Ham’s F12 medium supplemented with 10% fetal calf serum, non-essential amino acids (1 mM), insulin (10 μg/ml), penicillin (100 U/ml), and streptomycin (100 μg/ml).…”

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

“…Balabhadrapathruni et al [ 68 ] showed that a combination of BE-3-3-3 and the pure antiestrogen, ICI 182780 caused down-regulation of the anti-apoptotic Bcl-2 and Bcl-XL proteins and increased the level of the pro-apoptotic Bax protein in MCF-7 and T-47D breast cancer cells. The efficacy of polyamine analogues on breast cancer cells might be governed in part by their effects on the expression of proapoptotic and antiapoptotic proteins in these cells [ 69 ]. In the case of ERα-positive tumors, the involvement of genomic and non-genomic pathways has also to be considered in mechanistic studies [ 70 ].…”