N-(1-Pyrenyl) maleimide inhibits telomerase activity in a cell free system and induces apoptosis in Jurkat cells

Abstract

Telomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy. Agents that interact selectively with telomerase are anticipated to exert specific action on cancer cells. In this study, we evaluated maleimide derivatives for their potency and selectivity of telomerase inhibition. Among the several N-substituted derivatives of maleimide tested, N-(1-Pyrenyl) maleimide was shown to exert the greatest inhibition of telomerase in a cell free system, with an IC50 value of 0.25 μM. Importantly, we demonstrated that N-(1-pyrenyl) maleimide induces apoptosis in Jurkat T cells and displays the greatest differential cytotoxicity against hematopoietic cancer cells. These results suggest that N-(1-pyrenyl) maleimide is an attractive maleimide to be tested and developed as anti-cancer drug.

Exploring the mechanism of inhibition of human telomerase by cysteine‐reactive compounds

“…Finally, even if none of our compounds was really selective, we noticed that some of them could decrease telomerase activity in cancer cells cultured in vitro . As in previous studies , this was associated with a rapid cellular toxicity that is most probably not related to telomerase inhibition, as a comparable toxicity was observed on telomerase‐negative cell lines. In conclusion, our analysis supports the view that cysteine‐reactive molecules are a promising class of drug to efficiently inhibit telomerase, but highly specific inhibitors need to be developed to be able to target this enzyme by these class of reagents in humans.…”

“…1C). Similar observations have previously been reported for different [4][5][6][7], or somewhat related [3,15] telomerase inhibitors, and it has been speculated that these compounds function by binding to one or more unidentified cysteines. This putative mechanism of telomerase inhibition is indeed supported by the observation that maleimide, a well-known compound reacting preferentially with free cysteines at neutral pH, also inhibits telomerase activity in a DTT-sensitive manner (Fig.…”

“…In the past decades, several screening assays have been developed toward the identification of small‐molecule inhibitors . Among the compounds described, several of them have been proposed to function by the covalent binding to a cysteine residue . However, this hypothesis has never been confirmed by the direct detection of the adduct on the protein, and the putative position of the targeted residue(s) remains elusive.…”

N-(1-Pyrenyl) Maleimide Induces Bak Oligomerization and Mitochondrial Dysfunction in Jurkat Cells

“…During a search for anticancer drugs by screening for inhibitors of telomerase, we have identified several small molecule inhibitors, including helenalin [ 11 ] and maleimide-derived compound U-73122 [ 12 ] and N-(1-pyrenyl) maleimide (NPM) [ 13 ], that selectively inhibit telomerase in a cell-free system. One common feature of these compounds is that they are all thio-directed covalent modification agents.…”

Proteomic analyses of genes regulated by heterogeneous nuclear ribonucleoproteins A/B in Jurkat cells

“…Cell proliferation was determined by monitoring the increase of viable cells as a function of time by counting with hemocytometer. Apoptosis was assayed by the detection of phosphatidylserine exposure with FITC Annexin V Apoptosis Detection Kit I (BD Biosciences) using flow cytometry .…”