2024-03-28T13:17:08Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/747262021-12-27T16:01:38Zcom_10261_109com_10261_1col_10261_362
BH3-mimetics- and cisplatin-induced cell death proceeds through different pathways depending on the availability of death-related cellular components
Andreu-Fernández, Vicente
Genovés, Ainhoa
Messeguer Peypoch, Ángel
Orzáez, Mar
Sancho, Mónica
Pérez-Payá, Enrique
10 páginas, 7 figuras.
BACKGROUND: Owing to their important function in regulating cell death, pharmacological inhibition of Bcl-2 proteins by dubbed BH3-mimetics is a promising strategy for apoptosis induction or sensitization to chemotherapy. However, the role of Apaf-1, the main protein constituent of the apoptosome, in the process has yet not been analyzed. Furthermore as new chemotherapeutics develop, the possible chemotherapy-induced toxicity to rapidly dividing normal cells, especially sensitive differentiated cells, has to be considered. Such undesirable effects would probably be ameliorated by selectively and locally inhibiting apoptosis in defined sensitive cells.
METHODOLOGY AND PRINCIPAL FINDINGS: Mouse embryonic fibroblasts (MEFS) from Apaf-1 knock out mouse (MEFS KO Apaf-1) and Bax/Bak double KO (MEFS KO Bax/Bak), MEFS from wild-type mouse (MEFS wt) and human cervix adenocarcinoma (HeLa) cells were used to comparatively investigate the signaling cell death-induced pathways of BH3-mimetics, like ABT737 and GX15-070, with DNA damage-inducing agent cisplatin (cis-diammineplatinum(II) dichloride, CDDP). The study was performed in the absence or presence of apoptosis inhibitors namely, caspase inhibitors or apoptosome inhibitors. BH3-mimetic ABT737 required of Apaf-1 to exert its apoptosis-inducing effect. In contrast, BH3-mimetic GX15-070 and DNA damage-inducing CDDP induced cell death in the absence of both Bax/Bak and Apaf-1. GX15-070 induced autophagy-based cell death in all the cell lines analyzed. MEFS wt cells were protected from the cytotoxic effects of ABT737 and CDDP by chemical inhibition of the apoptosome through QM31, but not by using general caspase inhibitors.
CONCLUSIONS: BH3-mimetic ABT737 not only requires Bax/Bak to exert its apoptosis-inducing effect, but also Apaf-1, while GX15-070 and CDDP induce different modalities of cell death in the absence of Bax/Bak or Apaf-1. Inclusion of specific Apaf-1 inhibitors in topical and well-localized administrations, but not in systemic ones, to avoid interferences with chemotherapeutics would be of interest to prevent chemotherapeutic-induced unwanted cell death which could improve cancer patient care.
This work was supported by grants from the Spanish Ministry of Science and Innovation (MICINN - BIO2007-60066, SAF2010-15512, SAF2011-30542-C02-01 and CSD2008-00005C) and Generalitat Valenciana Prometeo 2010/005 (partially funded with ERDF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Peer reviewed
2013-04-19T11:31:56Z
2013-04-19T11:31:56Z
2013-02-21
artículo
http://purl.org/coar/resource_type/c_6501
PLoS ONE 8(2):e56881 (2013)
http://hdl.handle.net/10261/74726
10.1371/journal.pone.0056881
1932-6203
23437261
en
Publisher’s version
http://dx.doi.org/10.1371/journal.pone.0056881
open
Public Library of Science