Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/5792
Title: Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis
Authors: Custódio, José B. A. 
Cardoso, Carla M. P. 
Almeida, Leonor M. 
Keywords: Etoposide; Anticancer; Apoptosis; Mitochondrial permeability transition; Antioxidants; Oxidative stress
Issue Date: 2002
Citation: Chemico-Biological Interactions. 140:2 (2002) 169-184
Abstract: Etoposide (VP-16) is known to promote cell apoptosis either in cancer or in normal cells as a side effect. This fact is preceded by the induction of several mitochondrial events, including increase in Bax/Bcl-2 ratio followed by cytochrome c release and consequent activation of caspase-9 and -3, reduction of ATP levels, depolarization of membrane potential ([Delta][Psi]) and rupture of the outer membrane. These events are apoptotic factors essentially associated with the induction of the mitochondrial permeability transition (MPT). VP-16 has been shown to stimulate the Ca2+-dependent MPT induction similarly to prooxidants and to promote apoptosis by oxidative stress mechanisms, which is prevented by glutathione (GSH) and N-acetylcysteine (NAC). Therefore, the aim of this work was to study the effects of antioxidants and thiol protecting agents on MPT promoted by VP-16, attempting to identify the underlying mechanisms on VP-16-induced apoptosis. The increased sensitivity of isolated mitochondria to Ca2+-induced swelling, Ca2+ release, depolarization of [Delta][Psi] and uncoupling of respiration promoted by VP-16, which are prevented by cyclosporine A proving that VP-16 induces the MPT, are also efficiently prevented by ascorbate, the primary reductant of the phenoxyl radicals produced by VP-16. The thiol reagents GSH, dithiothreitol and N-ethylmaleimide, which have been reported to prevent the MPT induction, also protect this event promoted by VP-16. The inhibition of the VP-16-induced MPT by antioxidants agrees with the prevention of etoposide-induced apoptosis by GSH and NAC and suggests the generation of oxidant species as a potential mechanism underlying the MPT that may trigger the release of mitochondrial apoptogenic factors responsible for apoptotic cascade activation.
URI: https://hdl.handle.net/10316/5792
DOI: 10.1016/S0009-2797(02)00020-0
Rights: openAccess
Appears in Collections:FFUC- Artigos em Revistas Internacionais

Files in This Item:
File Description SizeFormat
filed137a22fb1134e428fd025e426b86dae.pdf286.39 kBAdobe PDFView/Open
Show full item record

SCOPUSTM   
Citations

34
checked on Mar 25, 2024

WEB OF SCIENCETM
Citations

31
checked on Mar 2, 2024

Page view(s) 50

545
checked on Mar 26, 2024

Download(s)

306
checked on Mar 26, 2024

Google ScholarTM

Check

Altmetric

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.