Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl)retinamide-induced apoptosis

Abstract

{We have studied the effect of N-(4-hydroxyphenyl)retinamide on either malignant human leukaemia cells or normal cells and investigated its mechanism of action. We demonstrate that 4HPR induces reactive oxygen species increase on mitochondria at a target between mitochondrial respiratory chain complex I and II. Such oxidative stress causes cardiolipin peroxidation which in turn allows cytochrome c release to cytosol, caspase-3 activation and therefore apoptotic consumption. Moreover, this apoptotic pathway seems to be bcl-2/bax independent and count only on malignant cells but not normal nor activated lymphocytes.

The sensitivity of the Ewing's sarcoma family of tumours to fenretinide-induced cell death is increased by EWS-Fli1-dependent modulation of p38MAPK activity

“…We have reported previously that the ROS-dependent phosphorylation of p38 MAPK is required for fenretinideinduced cell death in ESFT (Myatt et al, 2005), consistent with the hypothesis that induction of ROS is responsible for the selectivity of fenretinide for malignant cells (Asumendi et al, 2002;O'Donnell et al, 2002). The induction of ROS by fenretinide within an ESFT cell line, but not across ESFT cell lines, correlates with the degree of cell death observed following exposure to fenretinide.…”

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

“…JNK inhibitor suppresses cytochrome c release from mitochondria JNK has been shown to be required for cytochrome c release from mitochondria in stress-induced apoptosis (Tournier et al, 2000) and 4HPR has been shown to induce cytochrome c release from mitochondria in various cell types (Suzuki et al, 1999;Asumendi et al, 2002;Boya et al, 2003). To delineate the mechanism of JNK function in 4HPR-induced apoptosis in 22B cells, we examined the effect of SP600125 on mitochondrial events induced by 4HPR.…”

“…Increased generation of reactive oxygen species (ROS) (Delia et al, 1997;Suzuki et al, 1999;Hail and Lotan, 2001), increased ceramide production (Maurer et al, 1999), induction of mitochondrial permeability transition (MPT) (Suzuki et al, 1999;Hail and Lotan, 2000;Poot et al, 2002;Boya et al, 2003), cytochrome c release (Suzuki et al, 1999;Asumendi et al, 2002;Boya et al, 2003), increased GADD153 (Kim et al, 2002;Lovat et al, 2002), and activation of 12-lipoxygenase (Lovat et al, 2002) or activation of c-Jun N-terminal kinase (JNK) (Chen et al, 1999;Shimada et al, 2002;Osone et al, 2004) have been implicated in 4HPR-mediated apoptosis in various cancer cells. In addition, retinoid receptors may contribute to 4HPR-induced apoptosis in some cells (Sun et al, 1999;Lovat et al, 2000;Ulukaya et al, 2003).…”

Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells

“…4A show that 300 nmol/L CDDO-Me selectively depleted GSXm by 69% (P < 0.003) in KBM5 cells, and a similar effect was seen in KBM5-STI cells (65%; P < 0.02) after 3-h treatment without any marked effect in whole-cell GSX, supporting the notion that the triterpenoid structure of CDDO-Me may mediate perturbations in GSXm flux. Cardiolipin is the most abundant phospholipid in the mitochondrial membrane and has been shown to modulate the initiation of the intrinsic apoptotic pathway (29,30). Because GSXm is critical for the maintenance of cardiolipin (31 -33), we examined the levels of cardiolipin in cells treated with CDDO-Me by staining with the cardiolipin-selective fluorochrome nonyl acridine orange (NAO).…”