Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.
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PMID:Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells. 1547 62

Two relatively recent discoveries stand behind our current effort to investigate the effects of the chemopreventive agent, selenium, on the proliferation and survival of NB4 cells. The first is that certain selenium compounds such as sodium selenite have pro-oxidant ability to catalyze the oxidation of thiols and simultaneously generate superoxide. The second lies in the exquisite susceptibility of NB4 cells to arsenic trioxide-induced, reactive oxygen species (ROS)-mediated apoptosis due to less efficiency of the cellular defense system. In this study, we demonstrated that sodium selenite could induce apoptosis in NB4 cells via the classic mitochondrial pathway involving caspase-3 activation and Bcl-2 cleavage. An increase in the basal cellular glutathione (GSH) content rendered NB4 cells resistant to arsenic trioxide, but could sensitize NB4 cells to sodium selenite. Moreover, combined treatment of NB4 cells with all- trans retinoic acid (ATRA) at low concentration and sodium selenite exhibited a synergistic effect on apoptosis induction. Together, our results suggest that selenite is a promising candidate for treatment of acute promyelocytic leukemia (APL) and the mechanism underlying its anticancer effects warrants further investigation.
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PMID:Sodium selenite induces apoptosis in acute promyelocytic leukemia-derived NB4 cells by a caspase-3-dependent mechanism and a redox pathway different from that of arsenic trioxide. 1548 Jun 64

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10(-5) mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor kappaB (NFkappaB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFkappaB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.
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PMID:HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. 1549 66

The Sox6 gene is a member of the Sox gene family, which encodes transcription factors, and previous studies have suggested that it plays an important role in the development of the central nervous system. Aggregation of embryonic carcinoma P19 cells with retinoic acid (RA) results in the development of neurons, glia, and fibroblast-like cells. Sox6 mRNA increases rapidly in P19 cells during RA induction and then decreases during differentiation into neuronal cells. To investigate whether Sox6 expression is essential for neuronal differentiation, we established Sox6-suppressed P19 (P19[anti-Sox6]) cells by transfection of antisense-Sox6 cDNA. Most of the P19[anti-Sox6] cells showed no neurites and were not stained by the anti-MAP 2 antibody, while the suppression of Sox6 expression nearly totally blocked neuronal differentiation in P19 cells. Further, Sox6 suppression caused RA-dependent apoptosis by P19[anti-Sox6] cells: RA-treated P19[anti-Sox6] cells showed chromatin condensation, DNA fragmentation, and an increase in caspase-3-like activity. Thus, Sox6 is considered essential for neuronal differentiation and may play an important role in the early stages of neuronal differentiation or apoptosis.
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PMID:Suppression of Sox6 in P19 cells leads to failure of neuronal differentiation by retinoic acid and induces retinoic acid-dependent apoptosis. 1552 62

The promyelocytic leukemia RARalpha target gene encoding an adaptor molecule-1 (PRAM-1) is involved in a signaling pathway induced by retinoic acid in acute promyelocytic leukemia (APL) cells. To better understand the function of PRAM-1, we have undertaken the identification of its partners through a yeast two-hybrid screen. Here, we show that the proline-rich domain of PRAM-1 interacted with the Src homology 3 (SH3) domain of hematopoietic progenitor kinase 1 (HPK-1)-interacting protein of 55 kDa (HIP-55, also called SH3P7 and Abp1) known to stimulate the activity of HPK-1 and c-Jun N-terminal kinase (JNK). Overexpression of PRAM-1 in the NB4 APL cell line increased arsenic trioxide-induced JNK activation through a caspase 3-like-dependent activity. Dissociation of the SH3 domain from the rest of the HIP-55 protein was observed in the NB4 APL cell line treated with arsenic trioxide due to specific cleavage by caspase 3-like enzymes. The cleavage of HIP-55 correlated with the induction of PRAM-1 mRNA and protein expression. Taken together, our results suggest that the caspase 3-cleaved SH3 domain of HIP-55 is likely involved in PRAM-1-mediated JNK activation upon arsenic trioxide-induced differentiation of NB4 cells.
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PMID:PRAM-1 potentiates arsenic trioxide-induced JNK activation. 1563 62

To determine the effects of vitamin supplementation on the lipid-peroxidation-mediated toxicity of iron-ions on corneal endothelial cells (CECs) leading to apoptosis, murine CECs were maintained in tissue culture medium supplemented with increasing concentrations of free iron-ions, a treatment known to lead to increased lipid-peroxidation. The concentration of anti-oxidative vitamins (ascorbic acid, tocopherol and retinoic acid) in the cell supernatant and in the cells was determined by high-pressure liquid chromatography. Apoptosis was assessed by quantification of caspase-3-like activity and by using annexin-V/propidium iodide stains for flow cytometry. Lipid-peroxidation was measured by the malondialdehyde method. Supplementation with anti-oxidative vitamins was tested for the ability to counteract the induction of apoptosis. The production of nitric oxide was assessed spectrophotometrically and the expression levels of inducible and endothelial nitric oxide synthase were determined by Western blot. Increasing levels of free iron led to a rapid loss of anti-oxidative vitamins in the supernatant and in the CECs. This was correlated with rising levels of malondialdehyde and increased apoptosis. Supplementation with ascorbic acid or alpha-tocopherol alone did not prevent lipid-peroxidation in the cells. A combination of vitamins C and E (ascorbic acid, tocopherol) or solitary supplementation with vitamin A (retinoic acid) prevented lipid-peroxidation. We thus present a novel in vitro model for testing the direct influence of pro-oxidative species on CECs. We also show that supplementation with anti-oxidative vitamins to CECs significantly prevents the generation of free-radical-induced oxidative injury and apoptosis. These findings may have important implications for the storage of human corneae prior to transplantation and for the prolongation of corneal graft survival.
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PMID:Anti-oxidative vitamins prevent lipid-peroxidation and apoptosis in corneal endothelial cells. 1583 41

Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.
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PMID:Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans retinoic acid on the growth of cultured human pancreas cancer cells and pancreas tumor xenografts in immunodeficient mice. 1597 15

In a previous study, we reported an antileukaemic activity of auranofin (AF), demonstrating its dual effects: on the induction of apoptotic cell death and its synergistic action with retinoic acid on cell differentiation. In this study, we investigated the downstream signalling events of AF-induced apoptosis to determine the molecular mechanisms of AF activity. Treatment of HL-60 cells with AF induced apoptosis in a concentration- and time-dependent manner. Western blot analysis showed that AF-induced apoptosis was accompanied by the activation of caspase-8, caspase-9, and caspase-3, and the release of cytochrome c from the mitochondria. The phosphorylation and kinase activities of p38 mitogen-activated protein kinase (p38 MAPK) increased gradually until 12 h after AF (2 microM) treatment, and p38 MAPK was also activated concentration-dependently. Pretreatment with SB203580, a specific inhibitor of p38 MAPK, significantly blocked DNA fragmentation and the cleavage of procaspase-8, procaspase-3, and poly-ADP-ribose polymerase (PARP), whereas SB203580 alone had no effect. Reactive oxygen species (ROS) were also detected within 1 h after AF treatment, and the antioxidant N-acetyl-L-cysteine (NAC) effectively protected the cells from apoptosis by inhibiting the phosphorylation of p38 MAPK and the activation of caspases. These results suggest that ROS generation and the subsequent activation of p38 MAPK are essential for the proapoptotic effects of AF in human promyelocytic leukaemia HL-60 cells.
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PMID:The role of p38 MAPK activation in auranofin-induced apoptosis of human promyelocytic leukaemia HL-60 cells. 1608 31

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin found in grapes and wine, and has been reported to exert a variety of important pharmacological effects. We have investigated the activity of resveratrol on proliferation and differentiation of the acute promyelocytic leukemia cell line NB4. The growth inhibitory properties of resveratrol appear to be due to its induction of apoptotic cell death, as determined by morphological changes, DNA fragmentation, increased proportion of the subdiploid cell population and decreased mitochondrial transmembrane potential (Deltapsi(m)). Colorimetric assay for activity of caspase-3 showed an obvious increase in caspase-3 activity in cells after treatment with resveratrol. However, the expression levels of protein Bcl-2 and Bax show no significant change in response to resveratrol treatment. These results suggest that apoptosis of NB4 cells induced by resveratrol requires caspase-3 activation and is related to the mitochondrial transmembrane potential. The combination of resveratrol and all-tran-retinoic acid (ATRA) induced 100% of the NB4 cells to become NBT-positive, whereas only a small part of cells became positive for NBT after a similar exposure to either resveratrol or ATRA alone. Thus, resveratrol may be useful in treating acute promyelocytic leukemia.
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PMID:Resveratrol induces apoptosis and differentiation in acute promyelocytic leukemia (NB4) cells. 1608 38

The neural crest-derived mesectoderm gives rise to physiologic apoptosis areas in early vertebrate embryos. Certain teratologic agents increase this phenomenon. The purpose of this work was to detect caspase 3 (which is associated with the apoptosis cascade) and p53 in cell death areas, both during physiological apoptosis and during apoptosis induced by three agents (retinoic acid, methyl-triazene, irradiation). Antibody revelation was performed using the aBC peroxidase kit. Quantifications were also performed on histological sections. We observed caspase 3 uptake on some apoptotic and preapoptotic cells in control embryos, and in the embryos exposed to the three teratogens. Immunoreactivity generally preceded the development of cytological features of apoptosis. However, p53 was expressed only in the embryos exposed to ionizing radiation and methyl-triazene (an alkylating agent), but not significantly in embryos exposed to retinoic acid. The present results throw some light on apoptosis mechanisms in several teratologic conditions.
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PMID:[Expression of caspase 3 and p53 during physiological apoptosis and apoptosis induced by three teratologic agents during early craniofacial development of the mouse embryo]. 1611 Jul 44


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