We have recently found that D()lentiginosine, a synthetic iminosugar exerting glucosidase inhibitory activity, but not its natural enantiomer lentiginosine, is endowed with an unexpected, pro-apoptotic activity. Here, we investigated mechanisms involved in apoptosis induced by D()lentiginosine in MOLT-3, HT-29 and SH-SY5Y tumour cell lines. The results showed that D() lentiginosine increased caspase 9 expression at 18 h in all the cell lines from 1.5–3.1 folds. Cytochrome c in the cytoplasm was found to be increased from 2.3–2.6 folds in treated cells with respect to control cells. These effects were accompanied by a remarkable collapse of the mitochondrial membrane potential and by the downregulation of anti-apoptotic genes, as well as the upregulation of pro-apoptotic genes of the Bcl-2 family. U937Bcl-2 transfectants, highly expressing Bcl-2, were reluctant to undergo apoptosis even following treatment with 500 lM D()lentiginosine, whereas apoptosis by D()lentiginosine was induced also in U937 cells, naturally deficient in P53. Thus, our study establishes that the enantiomer of a natural iminosugar is endowed with a possible anti-tumorigenic effect that might be ascribed not only to their capacity to inhibit glycosidases but also to other unknown mechanisms. These data encourage further investigation on similar compounds to make them an interesting platform for the generation of new anticancer drugs.

D(-)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independent / A. Minutolo; S. Grelli; F. Marino-Merlo; F. M. Cordero; A. Brandi; B. Macchi; A. Mastino. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - ELETTRONICO. - 3(2012), pp. e358-e358. [10.1038/cddis.2012.97]

D(-)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independent

CORDERO, FRANCA MARIA;BRANDI, ALBERTO;
2012

Abstract

We have recently found that D()lentiginosine, a synthetic iminosugar exerting glucosidase inhibitory activity, but not its natural enantiomer lentiginosine, is endowed with an unexpected, pro-apoptotic activity. Here, we investigated mechanisms involved in apoptosis induced by D()lentiginosine in MOLT-3, HT-29 and SH-SY5Y tumour cell lines. The results showed that D() lentiginosine increased caspase 9 expression at 18 h in all the cell lines from 1.5–3.1 folds. Cytochrome c in the cytoplasm was found to be increased from 2.3–2.6 folds in treated cells with respect to control cells. These effects were accompanied by a remarkable collapse of the mitochondrial membrane potential and by the downregulation of anti-apoptotic genes, as well as the upregulation of pro-apoptotic genes of the Bcl-2 family. U937Bcl-2 transfectants, highly expressing Bcl-2, were reluctant to undergo apoptosis even following treatment with 500 lM D()lentiginosine, whereas apoptosis by D()lentiginosine was induced also in U937 cells, naturally deficient in P53. Thus, our study establishes that the enantiomer of a natural iminosugar is endowed with a possible anti-tumorigenic effect that might be ascribed not only to their capacity to inhibit glycosidases but also to other unknown mechanisms. These data encourage further investigation on similar compounds to make them an interesting platform for the generation of new anticancer drugs.
3
e358
e358
A. Minutolo; S. Grelli; F. Marino-Merlo; F. M. Cordero; A. Brandi; B. Macchi; A. Mastino
File in questo prodotto:
File Dimensione Formato  
CDDISLentiginosine.pdf

Accesso chiuso

Tipologia: Altro
Licenza: DRM non definito
Dimensione 685.94 kB
Formato Adobe PDF
685.94 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/648657
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 25
  • ???jsp.display-item.citation.isi??? 25
social impact