This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aleo, E. Articles by Brancolini, C. Search for Related Content PubMed PubMed Citation Articles by Aleo, E. Articles by Brancolini, C.

Identification of New Compounds That Trigger Apoptosome-Independent Caspase Activation and Apoptosis

Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia and MATI Center of Excellence, Universita' di Udine, Udine, Italy

Requests for reprints: Claudio Brancolini, Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia, Universita' di Udine. P.le Kolbe 4, 33100 Udine, Italy. Phone: 39-0432-494382; Fax: 39-0432-494301; E-mail: cbrancolini{at}makek.dstb.uniud.it.

Identification of alternative pathways of caspase activation is an important step to develop new antitumor treatments. We report here the result of a screening with a small chemical library, the Developmental Therapeutics Program-National Cancer Institute "challenge set," on cells expressing mutated caspase-9. We have identified two molecules capable of activating an apoptosome-independent apoptotic pathway. These compounds, named F6 and G5, target the ubiquitin-proteasome system by inhibiting the ubiquitin isopeptidases. We have shown that F6 and G5 induce a rather unique apoptotic pathway, which includes a Bcl-2-dependent but apoptosome-independent mitochondrial pathway with up-regulation of the BH3-only protein Noxa, stabilization of the inhibitor of apoptosis antagonist Smac, but also the involvement of the death receptor pathway. Noxa plays an important role in the induction of mitochondrial fragmentation and caspase activation, whereas the death receptor pathway becomes critical in the absence of a functional apoptosome. This study suggests that screening of chemical libraries on cancer cells with defined mutations in apoptotic key elements can lead to the identification of compounds that are useful to characterize alternative pathways of caspase activation. (Cancer Res 2006; 66(18): 9235-44)

This article has been cited by other articles:

				A. Fontanini, C. Foti, H. Potu, E. Crivellato, R. Maestro, P. Bernardi, F. Demarchi, and C. Brancolini The Isopeptidase Inhibitor G5 Triggers a Caspase-independent Necrotic Death in Cells Resistant to Apoptosis: A COMPARATIVE STUDY WITH THE PROTEASOME INHIBITOR BORTEZOMIB J. Biol. Chem., March 27, 2009; 284(13): 8369 - 8381. [Abstract] [Full Text] [PDF]

				C.-P. Lin, Y. Ban, Y. L. Lyu, S. D. Desai, and L. F. Liu A Ubiquitin-Proteasome Pathway for the Repair of Topoisomerase I-DNA Covalent Complexes J. Biol. Chem., July 25, 2008; 283(30): 21074 - 21083. [Abstract] [Full Text] [PDF]