Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic apoptosis-inducing retinoid with cancer chemopreventive properties and lower toxicity than all-trans retinoic acid. BAG-1 is an antiapoptotic gene that is overexpressed in cervical and other cancers. In this study, we examined whether BAG-1 can inhibit 4-HPR-induced apoptosis in the C33A cervical carcinoma cell line. Surprisingly, although it inhibited apoptosis induced by five different apoptotic stimuli, overexpression of BAG-1 enhanced apoptosis induced by 4-HPR, producing a 2.5-fold lower IC(50) of 4-HPR. The effects of BAG-1 on 4-HPR-induced apoptosis were mediated by enhancing the caspase-3 activation pathway. Deletion mutation experiments showed that the central ubiquitin homology domain of BAG-1 protein was necessary for its promotion of 4-HPR-induced apoptosis, whereas its C-terminal Hsp70/Hsc70-interacting domain was required for its inhibition of staurosporine-induced apoptosis. These in vitro results suggest that the effectiveness of 4-HPR against the development of malignancy may be due to the overexpression of BAG-1 in cancer cells.
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PMID:BAG-1 promotes apoptosis induced by N-(4-hydroxyphenyl)retinamide in human cervical carcinoma cells. 1077 21

4-HPR (fenretinide) is a synthetic analog of retinoic acid (RA) whose potential as a chemopreventative agent has gained support from in vitro and animal experiments and in limited clinical trials. Comparative analyses of cellular, biochemical, and molecular properties of fenretinide with RA using various tissue culture cells reveal that a key distinction between these two retinoids lies in the ability of fenretinide to induce programmed cell death, also known as apoptosis. Here we review the composite evidence for induction of apoptosis in fenretinide-treated cells. Assays used to validate apoptosis in various cell types are also summarized. Apoptosis in response to fenretinide primarily occurs by a receptor-independent mechanism, which is accompanied by increases in signaling molecules, e.g., ceramide, and cysteine-dependent aspartate-directed proteases, termed caspases, including execution caspase-3. Both caspase-3 inhibitor DEVD-CHO and ceramide synthase inhibitor fumonisin B(1) (FB(1)) block fenretinide-induced apoptosis. Increase in caspase-3 appears to result from fenretinide-elicited stabilization of procaspase-3 zymogen. We also review apoptotic regulatory proteins such as inhibitor of apoptosis (IAPs) and second mitochondria-derived activator of caspase (SMACs) that participate in the coordinate control of caspase activities. The existence of a large number of proteins capable of modulating apoptosis via activation or inhibition of caspases, coupled with the fact that both the initiation and execution phases of apoptosis utilize pre-existing zymogens, which, once set in motion, culminates in an irreversible apoptotic cascade, raise the possibility that the on/off switch of apoptosis is linked to an intricate intracellular regulatory network, capable of responding to external stimuli such as fenretinide. This network functions to provide checks/balances of the need for apoptosis as well as to minimize and prevent untimely errors in apoptosis. We suggest that dynamic and coordinated regulation of apoptosis by such a hypothetical network in vivo may involve co-localization of pro- and anti-apoptotic proteins and their respective activators/inhibitors in a macromolecular modular unit which we propose to be named caspasomes. Fenretinide also induces apoptosis by elevating reactive oxygen species (ROS), unrelated to changes in ceramide-caspases. Thus multiple, distinct pathways contribute to the induction of apoptosis by fenretinide.
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PMID:Mechanism of fenretinide (4-HPR)-induced cell death. 1148 62

We observed that N-(4-hydroxyphenyl)retinamide (4HPR), a chemopreventive and chemotherapeutic agent, effectively induced apoptosis in hepatoma cells. Interestingly, Fas-negative (Hep 3B and PLC/PRF/5) hepatoma cells were shown to be more susceptible to apoptosis induced by 4HPR than were Fas-positive (Hep G2 and SK-HEP-1) hepatoma cells. Thus, we explored the mechanisms underlying 4HPR-induced apoptosis in Fas-defective hepatoma cells. Hep 3B cells stably expressing the dominant-negative Fas-associated death domain (dnFADD) showed no alteration in 4HPR drug susceptibility, but when stably expressing E1B19K, Crm A, or dominant-negative FLICE (dnFLICE), Hep 3B cells were resistant, suggesting that 4HPR-induced apoptosis was mediated by caspase-8 activation. Furthermore, apoptosis could be completely blocked by Z-VAD-FMK (a general caspase inhibitor) or by IETD-CHO (a caspase-8 inhibitor), but was only partially blocked by Ac-DEVD-CMK (a caspase-3 inhibitor), by N-acetyl-L-cysteine (NAC) (an antioxidant), by N-acetyl-leucyl-leucyl-norleucinal (ALLN) (a calpain inhibitor I), or by Z-LEHD-FMK (a caspase-9 inhibitor). Time-sequence analysis of the induction of apoptosis by 4HPR revealed that an initial caspase-8 activation was followed by late mitochondrial cytochrome c release and minor caspase-9 activation, which suggested that caspase-8 activation is the primary upstream regulatory point. Activation of Bid or induction of proapoptotic Bax was not observed during apoptosis. In contrast, Bcl-xL expression was decreased during 4HPR-induced apoptosis. Taken together, these results indicate that 4HPR may be a potential chemotherapeutic drug, which is able to induce apoptosis in Fas-defective hepatoma cells through caspase-8 activation.
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PMID:Activation of caspase-8 during N-(4-hydroxyphenyl)retinamide-induced apoptosis in Fas-defective hepatoma cells. 1173 1

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.
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PMID:Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl)retinamide-induced apoptosis. 1208 92

Retinoids have great promise in the area of cancer therapy and chemoprevention. Although some tumor cells are sensitive to the growth inhibitory effect of all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-((1-Admantyl)-4-hydroxyphenyl)-2-naphthalenecarboxylic acid (CD437) is a conformationally restricted synthetic retinoid that induces growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. To better understand the mechanism by which CD437 induces apoptosis in ovarian tumor cell lines, we prepared a cell line, CA-CD437R, from the ATRA-sensitive ovarian cell line, CA-OV-3, which was resistant to CD437. We found that the CD437-resistant cell line was also resistant to the induction of apoptosis by tumor necrosis factor-alpha but not resistant to the induction of apoptosis by another synthetic retinoid, fenretinide N-(4-hydroxyphenyl)retinamide. We also show that this cell line remains ATRA-sensitive and exhibits no deficiencies in RAR function. Analysis of this CD437-resistant cell line suggests that the pathway for induction of apoptosis by CD437 is similar to the pathway utilized by tumor necrosis factor-alpha and different from the pathway induced by the synthetic retinoid, fenretinide N-(4-hydroxyphenyl)retinamide. The CA-CD437R cell line is a valuable tool, permitting us to further elucidate the molecular events that mediate apoptosis induced by CD437 and other synthetic retinoids. Results of experiments utilizing this cell line suggest that the alteration responsible for resistance of CA-CD437R cells to CD437 induced event maps after the activation of p38 and TR3 expression, prior to mitochondrial depolarization, subsequent release of cytochrome c and activation of caspase-9 and caspase-3.
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PMID:Elucidation of molecular events mediating induction of apoptosis by synthetic retinoids using a CD437-resistant ovarian carcinoma cell line. 1223 93

Retinoids that regulate cell growth, differentiation, and apoptosis have shown promising results in preclinical studies and in a few clinical trials of cancer chemoprevention and therapy. However, the clinical use of retinoids is limited by resistance of certain malignant cells to their antitumor effects and by side effects. To identify more potent retinoids, we examined the effects of heteroarotinoids (Hets), new synthetic retinoids with reduced toxicity, on the growth of human head and neck squamous cell carcinoma (HNSCC) lines. Six Hets with different retinoic acid receptor activation potentials were found to exhibit distinct efficacies. The most potent among the Hets examined, SHetA2, [[(4-nitrophenyl)amino][2,2,4,4-tetramethyl thiochroman-6-yl)amino] methane-1-thione], was more effective than either all-trans- or 9-cis-RA. The growth of UMSCC38, the most sensitive among the eight HNSCC cell lines examined, was suppressed by ShetA2 in a dose- and time-dependent fashion. SHetA2-induced apoptosis in UMSCC38 cells was comparable with N-(4-hydroxyphenyl)retinamide (4HPR). Reactive oxygen species (ROS) generation in the UMSCC38 cells was increased by SHetA2, and this effect was suppressed by the antioxidant butylated hydroxyanisol, which also suppressed SHetA2-induced apoptosis. SHetA2 suppressed mitochondrial permeability transition and enhanced cytochrome c release from mitochondria. Both of these effects were prevented by cyclosporin A, which also decreased SHetA2-induced apoptosis. SHetA2 increased caspase-3-like activity, and a caspase-3 inhibitor diminished SHetA2-induced apoptosis. Several retinoid receptor antagonists failed to prevent apoptosis induction by SHetA2. These results demonstrate that SHetA2 is a potent, receptor-independent, apoptosis inducer that acts on the mitochondria in HNSCC cells. Further investigation of the potential of SHetA2 in prevention and therapy of HNSCC is warranted also because of much lower toxicities compared with receptor active retinoids.
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PMID:The synthetic heteroarotinoid SHetA2 induces apoptosis in squamous carcinoma cells through a receptor-independent and mitochondria-dependent pathway. 1283 80

Synthetic retinoid-related molecules, such as N-(4-hydroxyphenyl)retinamide (fenretinide) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induce apoptosis in a variety of malignant cells. The mechanism(s) of action of these compounds does not appear to involve retinoic acid receptors (RARs) and retinoid X receptors (RXRs), although some investigators disagree with this view. To clarify whether some retinoid-related molecules can induce apoptosis without involving RARs and/or RXRs, we used 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-E-propenyl] benzoic acid (AGN193198) that neither binds effectively to RARs and RXRs nor transactivates in RAR- and RXR-mediated reporter assays. AGN193198 potently induced apoptosis in prostate, breast, and gastrointestinal carcinoma cells and in leukemia cells. AGN193198 also abolished growth (by 50% at 130-332 nM) and induced apoptosis in primary cultures established from prostatic carcinoma (13 patients) and gastrointestinal carcinoma (1 patient). Apoptosis was induced rapidly, as indicated by mitochondrial depolarization and DNA fragmentation. Molecular events provoked by AGN193198 included activation of caspase-3, -8, -9, and -10 (by 4-6 h) and the production of BID/p15 (by 6 h). These findings show that caspase-mediated induction of apoptosis by AGN193198 is RAR/RXR-independent and suggest that this compound may be useful in the treatment of prostate cancer.
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PMID:A retinoid-related molecule that does not bind to classical retinoid receptors potently induces apoptosis in human prostate cancer cells through rapid caspase activation. 1512 74

The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) induces apoptosis in a variety of human cancer cells including breast carcinoma and this property may be important for its chemopreventive and therapeutic effects. Resistance to 4HPR has been described, however, the molecular mechanisms underlying sensitivity or resistance to this retinoid are not clear. Recently, it has been shown that the carbohydrate-binding protein galectin-3, which has been implicated in tumor progression, contains the anti-death motif NWGR present in the anti-apoptotic protein Bcl-2. To determine whether galectin-3 expression can abrogate the effect of 4HPR, we tested the effects of 4HPR on apoptosis of cell clones derived from the galectin-3 deficient human BT549 breast carcinoma cells after transfection with either wild type galectin-3 (BT549Gal-3Wt), galectin-3 inactivated by a point mutation in the NWGR motif (BT549Gal-3Mu), or empty vector control (BT549Vec). Both BT549Vec and BT549Gal-3Mu cells showed a marked decrease in survival after treatment with 4HPR principally due to induction of apoptosis. 4HPR-induced apoptosis in these cells was associated with stimulation of reactive oxygen species generation, decreased levels of Bcl-2 protein, release of cytochrome c into the cytosol, increased caspase-3 activity, and poly(ADP-ribose) polymerase cleavage. In contrast, 4HPR failed to exert any of these effects in the BT549Gal-3Wt cells. The demonstration that galectin-3 suppresses 4HPR-induced apoptosis in human breast carcinoma cells suggests that the increased expression of galectin-3 during cancer progression may be associated with 4HPR resistance.
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PMID:Inhibition of N-(4-hydroxyphenyl)retinamide-induced apoptosis in breast cancer cells by galectin-3. 1532 75

Celecoxib exhibits cancer preventive and therapeutic effects in animal models and clinical trials. It presumably acts through selective inhibition of cyclooxygenase-2 (COX-2) and subsequent reduction of prostaglandin (PG) synthesis. However, the concentrations of celecoxib required for growth inhibition and apoptosis induction in vitro are higher than those needed for suppression of PGs. Moreover, those concentrations are not achievable in humans raising a controversy regarding the clinical relevance of in vitro data. We investigated the activity of celecoxib alone and in combination with the pro-apoptotic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) on growth and apoptosis of human nonsmall cell lung cancer (NSCLC) cell lines. Celecoxib inhibited growth of thirteen NSCLC cell lines with IC50 values ranging from 19 to 33 microM regardless of their COX-2 expression. Apoptosis was induced in cells with high (A549) as well as low (H1792) COX-2 levels but only at a concentration of 75 microM celecoxib. However, treatment with pharmacologically feasible concentrations of celecoxib (< or = 10 microM) in combination with 4HPR (< or = 2 microM) resulted in a marked suppression of NSCLC cell growth and colony formation. Apoptosis mediated by activation of caspase-3, cleavage of PARP and lamin A was suppressed by addition of antioxidants, suggesting that the generation of reactive oxygen species was partially involved. This study indicates, that celecoxib combined with 4HPR is more effective than treatment with either agent alone in inhibition of growth and induction of apoptosis in NSCLC cells. It suggests further investigations of this combination for lung cancer treatment.
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PMID:Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations. 1622 24

N-(4-hydroxyphenyl) retinamide (4-HPR, fenretinide) a synthetic retinoid is in clinical trials for the treatment of several malignancies. However, its biological effects and therapeutic value in childhood brain tumor medulloblastoma (MB) has not been investigated. In this study, we report for the first time that fenretinide (2.5-10 microM) induces apoptotic cell death in human MB cells. We observed significant inhibition of cell survival in four MB cell lines (D425MED, D458MED, D283MED and D341MED) as determined by MTT assays. These results were further supported by inhibition of anchorage-independent colony formation in soft agar. Fenretinide-induced decrease in cell viability was in part due to activation of caspase-3 dependent cell death, which was further supported by the cleavage of poly(ADP-ribose) polymerase-1 (PARP-1), a caspase-3 substrate. Cell death was partially prevented by the antioxidant, l-ascorbic acid suggesting that free radical intermediates might be involved in fenretinide effects. These results suggest that pharmacologically achievable concentrations of fenretinide are effective in killing MB cells and thus show its therapeutic potential to treat human MB.
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PMID:Anticancer effects of fenretinide in human medulloblastoma. 1639 27


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