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)

Berberine, an isoquinoline plant alkaloid, is known to generate a wide variety of biochemical and pharmacological effects. To elucidate the molecular mechanism of berberine-induced antiproliferative activities, the human promonocytic U937 cells were used. Berberine exhibited dose-dependent antiproliferative effects. Morphological evidence of apoptosis, including apoptotic DNA fragmentation, were observed in cells treated with 75 microg ml(-1) of berberine for 24h. Flow cytometry analysis revealed that berberine had no effect on cell cycle profile of U937 cells, however, sub-G(0) fraction (apoptotic cell population) was detected. The percentage of sub-G(0) fraction of cells treated with 75 microg ml(-1) of berberine was 25.3+/-1.6%. Berberine induces significant changes in mitochondrial membrane potential of U937 cells. The highest tested concentration of berberine decreased the mitochondrial membrane potential to 15.8+/-2.4% of control. Additionally, berberine-treated cells had an elevated level of ROS production. Activation of caspase-9 and caspase-3 was also detected, with no caspase-8 activation observed. Taken together, the results clearly demonstrate that berberine induces apoptosis of U937 cells through the mitochondrial/caspase-dependent pathway.
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PMID:Berberine induces apoptosis through a mitochondrial/caspase pathway in human promonocytic U937 cells. 1701 Nov 59

Caspase-3 is a programmed cell death protease involved in neuronal apoptosis during physiological development and under pathological conditions. It is a promising therapeutic target for treatment of neurodegenerative diseases. We reported previously that isoquinoline-1,3,4-trione and its derivatives inhibit caspase-3. In this report, we validate isoquinoline-1,3,4-trione and its derivatives as potent, selective, irreversible, slow-binding and pan-caspase inhibitors. Furthermore, we show that these inhibitors attenuated apoptosis induced by beta-amyloid(25-35) in PC12 cells and primary neuronal cells.
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PMID:Isoquinoline-1,3,4-trione and its derivatives attenuate beta-amyloid-induced apoptosis of neuronal cells. 1703 54

Cisplatin is one of the primary drugs utilized in the treatment of ovarian cancer. However, despite the initial effectiveness of chemotherapy in suppressing this disease, drug resistance almost invariably develops and cures are relatively rare. While it is generally thought that only compounds of the cis geometry express antitumor activity, a number of transplatinum derivates have shown preclinical promise. The current work investigates the influence of transplanaramine (TPA) compounds of structure trans-[Pt (O(2)CR)(2) (L) (L')], (L=NH(3), L'=pyridine, quinoline, isoquinoline; L=L'=pyridine; R=H, CH(3), CH(2)OH, etc.) (with a focus on the contribution of the carboxylate leaving group to drug action) on growth and viability of A2780 human ovarian carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The compounds, as a class, induce cell death through caspase-dependent apoptosis, with activation of both caspase 3 and caspase 9 and concomitant PARP cleavage. The trans-platinum compounds tested show induction of p53 as well as time dependent gammaH2AX induction, consistent with the promotion of DNA lesions. trans-[Pt(O(2)CH)(2)(NH(3))(4-pic)] can be shown to promote significant DNA strand breaks and DNA interstrand cross-linking. The enhanced cytotoxicity of trans-[Pt(O(2)CH)(2)(NH(3))(4-pic)] compared to its isostructural -O(2)CCH(3) and -O(2)CCH(2)OH analogs may be a consequence of its accelerated cellular accumulation, increased hydrolytic activation, interstrand cross-linking and abortive efforts by the cell to repair the cross linked DNA.
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PMID:Promotion of DNA strand breaks, interstrand cross-links and apoptotic cell death in A2780 human ovarian cancer cells by transplatinum planar amine complexes. 1741 17

Caspase-1, the most efficient enzyme in processing the proinflammatory cytokines interleukin 1beta and interleukin 18 in humans, is associated with inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and some neuronal diseases. We previously reported that isoquinoline-1,3,4-trione and its derivatives are novel caspase-3 inhibitors that could attenuate apoptosis in vitro and in vivo. Here we report a novel derivative of isoquinoline-1,3,4-trione that is highly potent in inhibiting caspase-1 activity in an irreversible and slow-binding manner, thus inhibiting cellular caspase-1 activity and the maturation of interleukin 1beta in U-937 cells.
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PMID:Novel irreversible caspase-1 inhibitor attenuates the maturation of intracellular interleukin-1beta. 1746 45

Berberine, an isoquinoline alkaloid, has been shown to possess anticancer properties in some cancer cell lines. Here, we report that in vitro treatment of cervical cancer Ca Ski cells with berberine decreased the percentage of viable Ca Ski cells in a dose-dependent and time-dependent manner. Berberine enhanced the apoptosis of Ca Ski cells with the induction of a higher ratio of p53 and Bax/Bcl-2 proteins, increased levels of reactive oxygen species (ROS) and Ca2+, disruption of the mitochondrial membrane potential, and promotion of caspase-3 activity. In CaSki cells pretreated with the pan-caspase inhibitor zVAD-fmk, the berberine-induced caspase-3 activity and apoptosis were significantly blocked as confirmed by flow cytometric analysis. Western blot also showed that berberine induced the expression of GADD153, a transcription factor involved in apoptosis. Thus berberine increased ROS levels leading to endoplasmic reticulum (ER) stress based on the increase of GADD153 and shown by Ca2+ release from the ER. When the Ca Ski cells were pretreated with catalase, GADD153 production was abrogated and apoptosis was significantly reduced.
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PMID:GADD153 mediates berberine-induced apoptosis in human cervical cancer Ca ski cells. 1797 84

Berberine, an isoquinoline alkaloid isolated from several medicinal plants, has been reported to possess anti-bacterial, anti-inflammatory and antitumor properties. Although berberine also inhibits osteoclastogenesis and bone resorption, the molecular machinery for its inhibitory effects remains unknown. This study focused on the suppressive effects of berberine on receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL)-induced osteoclastogenesis and survival. Berberine inhibited RANKL-mediated osteoclast formation and survival while having no cytotoxic effects on bone marrow macrophages or osteoblastic cells. Berberine attenuated RANKL-induced activation of NF-kappaB through inhibiting phosphorylation at the activation loop of IkappaBalpha kinase beta, phosphorylation and degradation of IkappaBalpha, and NF-kappaB p65 nuclear translocation. RANKL-induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte/macrophage-colony stimulating factor (M-CSF)-induced nor insulin-induced Akt activation was inhibited by the drug. Under M-CSF- and RANKL-deprived condition, berberine increased the active form of caspase-3 in osteoclasts. By contrast, berberine did not potentiate the activation of caspase-3 in M-CSF-deprived bone marrow macrophages. These findings indicate that berberine inhibits osteoclast formation and survival through suppression of NF-kappaB and Akt activation and that both pathways in the osteoclast lineage are highly sensitive to berberine treatment.
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PMID:Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways. 1808 61

Berberine is an isoquinoline plant alkaloid with a long history of being used for the treatment of many diseases in Chinese herbal medicine. Berberine has a wide range of biochemical and pharmacological effects, including antitumor activities, but its mechanism of action is not clearly understood. In this study, we investigated that the relationship between the antiproliferative activities of berberine and the apoptotic pathway associated with its molecular mechanism of action in human glioblastoma T98G cells. Berberine treatment of T98G cell lines inhibited cell proliferation and induced cell death in a dose (50-200 microg/ml) dependent manner with an IC50 value of 134 microg/ml, which was associated with an increase in G1 arrest. Western blot analysis showed that the berberine-induced G1 arrest was mediated through the increased expression of P27 and the decreased expression of cyclin-dependent kinase (CDK) 2, CDK4, cyclin D, and cyclin E proteins. Berberine treatment also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of the Bax/Bcl-2 proteins, the disruption of mitochondrial membrane potential, and the activation of procaspase-9, caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). Berberine can inhibit T98G cell proliferation by inducing G1 arrest and apoptosis. These results demonstrate that the berberine-induced apoptosis of T98G cells is primarily mediated through the mitochondrial/caspases-dependent pathway.
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PMID:Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. 1837 40

Caspase-3 is an attractive therapeutic target for treatment of diseases involving disregulated apoptosis. We report here the mechanism of caspase-3 inactivation by isoquinoline-1,3,4-trione derivatives. Kinetic analysis indicates the compounds can irreversibly inactivate caspase-3 in a 1,4-dithiothreitol (DTT)- and oxygen-dependent manner, implying that a redox cycle might take place in the inactivation process. Reactive oxygen species detection experiments using a chemical indicator, together with electron spin resonance measurement, suggest that ROS can be generated by reaction of isoquinoline-1,3,4-trione derivatives with DTT. Oxygen-free radical scavenger catalase and superoxide dismutase eliciting the inactivation of caspase-3 by the inhibitors confirm that ROS mediates the inactivation process. Crystal structures of caspase-3 in complexes with isoquinoline-1,3,4-trione derivatives show that the catalytic cysteine is oxidized to sulfonic acid (-SO(3)H) and isoquinoline-1,3,4-trione derivatives are bound at the dimer interface of caspase-3. Further mutagenesis study shows that the binding of the inhibitors with caspase-3 appears to be nonspecific. Isoquinoline-1,3,4-trione derivative-catalyzed caspase-3 inactivation could also be observed when DTT is substituted with dihydrolipoic acid, which exists widely in cells and might play an important role in the in vivo inactivation process in which the inhibitors inactivate caspase-3 in cells and then prevent the cells from apoptosis. These results provide valuable information for further development of small molecular inhibitors against caspase-3 or other oxidation-sensitive proteins.
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PMID:Isoquinoline-1,3,4-trione derivatives inactivate caspase-3 by generation of reactive oxygen species. 1876 68

Berberine, an isoquinoline plant alkaloid, has been known to generate a wide variety of biochemical and pharmacological effects. In order to elucidate the molecular mechanism for the berberine-induced enhancement of radio-sensitization, the human hepatoma HepG2 cells were treated with berberine combined with irradiation. The anti-tumor effect of gamma radiation was found to be significantly enhanced by berberine. The evidences of apoptosis, such as apoptotic DNA fragmentation and annexin V staining, were observed in the cells treated with the combination of berberine and irradiation. Additionally, the levels of reactive oxygen species (ROS) and nitric oxide (NO) were apparently elevated in the combination system. The activations of p38, Bax, and caspase-3 were also detected in the irradiated cells pretreated with berberine. The productions of ROS and annexin V staining in the cells treated with the combination of berberine and irradiation were significantly inhibited by the specific inhibitor of p38 MAPK, SB203580. The cell death induced by berberine alone or the combination of berberine and irradiation was suppressed by the anti-oxidant, N-acetyl cysteine (NAC). Taken together, the present results clearly indicate that the combination of berberine and gamma-radiation enhance the anti-cancer effects through the p38 MAPK pathway and ROS generation.
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PMID:The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. 1949 7

Poly(ADP-ribose)polymerase-1 (PARP-1) is thought to be required for apoptosis-inducing factor (AIF) release from mitochondria in caspase-independent apoptosis. The mechanism by which AIF is released through PARP-1 remains unclear. Here, we provide evidence that PARP-1-independent AIF release and cell death are induced by a trienoic fatty acid, alpha-eleostearic acid (alpha-ESA). Alpha-ESA induced the caspase-independent and AIF-initiated apoptotic death of neuronal cell lines, independently of PARP-1 activation. The cell death was inhibited by the MEK inhibitor U0126 and by knockdown of MEK using small interfering RNA. However, inhibitors for JNK, p38 inhibitors, calpain, phospholipase A(2), and phosphatidylinositol 3-kinase, did not block cell death. AIF was translocated to the nucleus after the induction of apoptosis by alpha-ESA in differentiated PC12 cells without activating caspase-3 and PARP-1. The alpha-ESA-mediated cell death was not inhibited by PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinoline and by knockdown of PARP-1 using small interfering RNA. Unlike N-methyl-N'-nitro-N-nitrosoguanidine treatment, histone-phosphorylated histone 2AX was not phosphorylated by alpha-ESA, which suggests no DNA damage. Overexpression of Bcl-2 did not inhibit the cell death. alpha-ESA caused a small quantity of superoxide production in the mitochondria, resulting in the reduction of mitochondrial membrane potential, both of which were blocked by a trace amount of alpha-tocopherol localized in the mitochondria. Our results demonstrate that alpha-ESA induces PARP-1-independent AIF release and cell death without activating Bax, cytochrome c, and caspase-3. MEK is also a key molecule, although the link between ERK, AIF release, and cell death remains unknown. Finding molecules that regulate AIF release may be an important therapeutic target for the treatment of neuronal injury.
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PMID:Poly(ADP-ribose) polymerase (PARP)-1-independent apoptosis-inducing factor (AIF) release and cell death are induced by eleostearic acid and blocked by alpha-tocopherol and MEK inhibition. 2017 52


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