Potential small-molecule activators of caspase-7 identified using yeast-based caspase-3 and-7 screening assays

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Clara Pereira (Author) Other; Vanessa Lopes Rodrigues (Author) Other; Isabel Coutinho (Author) Other; Marta P Neves (Author) Other; Raquel T Lima (Author) Other; Madalena Pinto (Author) FFUP; Honorina Cidade (Author) FFUP; Helena H Vasconcelos (Author) FFUP; Lucilia Saraiva (Author) FFUP

Journal

Title: European Journal of Pharmaceutical Sciences

Vol. 54

Pages: 8-16

ISSN: 0928-0987

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 10 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-009-6VA

DOI: 10.1016/j.ejps.2013.12.017

Abstract (EN): Caspases-3 and -7 are at the core of the execution phase of apoptosis. The search for activators of these proteases has therefore deserved particular attention in the field of anticancer drug discovery. Here, a simplified yeast-based screening approach was developed and used to search for activators of caspases-3 and -7, followed0 by evaluation of the activity of the selected compounds in the human tumor cell lines HL-60 (acute promyelocytic leukemia) and MCF-7 (breast adenocarcinoma). By using the yeast approach, two potential activators of caspase-7, 5,6-dihydroxy-7-prenyloxyflavone (la) and 3-hydroxy-7-geranyloxyflavone (2a), were identified. Unlike the known caspases-3 and -7 activator, the procaspase activating compound-1 (PAC-1), these flavonoids did not interfere with the caspase-3 activity in yeast. Moreover, flavonoids la and 2a processed procaspase-7 to the active caspase-7 both in yeast and in vitro processing assays, and inhibited the growth of HL-60 and MCF-7 human tumor cells with higher potencies than PAC-1, particularly in the absence of caspase-3 (MCF-7 cells). In MCF-7 cells, the flavonoids processed procaspase-7, increased its activity and sensitized these cells to the effects of the cytotoxic drug, etoposide. In conclusion, the developed yeast target-based screening assays led to the identification of potential caspase-7 activators. A proof of concept is therefore provided for the effectiveness of the yeast assays in the discovery of caspase activators. Additionally, the identified compounds may pave the way for a new class of caspase activators with improved anticancer properties.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9