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)

Chemotherapy agents initiate tumour cell apoptosis and this is thought to involve oxidative stress. In this study we have investigated the effect of the important antioxidant Vitamin C (ascorbate) on the response of HL60 and Jurkat cells to three chemotherapy drugs, namely etoposide, melphalan and arsenic trioxide (As(2)O(3)). Cells grown in routine culture media are deficient in ascorbate and to determine its effect on chemotherapy drug-induced apoptosis we supplemented the cells prior to drug exposure. We found that ascorbate had a varied effect on apoptosis and cell cycle progression. Etoposide-induced apoptosis in HL60 cells was significantly increased in ascorbate-loaded cells as measured by caspase-3 activation and DNA degradation, and this appeared to reflect a decrease in the number of necrotic cells rather than increased cytotoxicity. In contrast, ascorbate had no effect on etoposide-induced apoptosis in Jurkat cells. In both cell types melphalan-induced apoptosis was unaffected by intracellular ascorbate, whereas both apoptosis and growth arrest with low concentrations of As(2)O(3) were diminished. These results indicate that intracellular ascorbate can affect cell responses to chemotherapy drugs in a complex and somewhat unpredictable manner and that it may play an important role in the responsiveness of tumour cells to chemotherapy regimes.
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PMID:The effect of intracellular ascorbate on the susceptibility of HL60 and Jurkat cells to chemotherapy agents. 1695 22

Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8- and 2.6-fold decrease in cell proliferation, respectively) (P<0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8- and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (P<0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 microg ml(-1) VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 microg ml(-1) VP-16 (P<0.001). VP-16 enhanced the release of IL-1beta and TNF-alpha from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (P<0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.
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PMID:Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells. 1704 52

Etoposide (VP-16) belongs to the family of DNA topoisomerase II (topo2) inhibitors, drugs widely used in cancer chemotherapy. Their presumed mode of action is stabilization of "cleavable complexes" between topo2 and DNA; collisions of DNA replication forks with these complexes convert them into DNA double-strand breaks (DSBs), potentially lethal lesions that may trigger apoptosis. Immunocytochemical detection of activation of ATM (ATM-S1981P) and histone H2AX phosphorylation (gammaH2AX) provides a sensitive probe of the induction of DSBs in individual cells. Using multiparameter cytometry we measured the expression of ATM-S1981P and gammaH2AX as well as initiation of apoptosis (caspase-3 activation) in relation to the cell cycle phase in etoposide-treated human lymphoblastoid TK6 cells. The induction of ATM-S1981P and gammaH2AX was seen in all phases of the cell cycle. The G(1)-phase cells, however, preferentially underwent apoptosis. The extent of etoposide-induced H2AX phosphorylation was partially reduced by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS). The maximal reduction of H2AX phosphorylation by NAC, seen in G(1)-phase cells, was nearly 50%. NAC also protected a fraction of G(1) cells from etoposide-induced apoptosis, but had no such effect on S or G(2)M cells. However, no significant rise in the intracellular level of ROS upon treatment with etoposide was detected. The effects of etoposide were compared with the previously investigated effects of another topo2 inhibitor, mitoxantrone. The latter was seen to induce a maximal level of ATM-S1981P and gammaH2AX (partially abrogated by NAC) in G(1)-phase cells, but unlike etoposide, triggered apoptosis exclusively of S-phase cells. The data suggest that in addition to the generally accepted mechanism involving collisions of replication forks with the "cleavable complexes", other mechanisms which appear to be different for etoposide vs. mitoxantrone, may contribute to formation of DSBs and to triggering of apoptosis.
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PMID:Induction of ATM activation, histone H2AX phosphorylation and apoptosis by etoposide: relation to cell cycle phase. 1729 10

Apoptotic cell death is a highly regulated process, which plays a crucial role in many biological events. Etoposide is an antineoplastic drug, which targets the DNA unwinding enzyme, topoisomerase II. The aim of the present research approach to investigate the expression of the apoptosis-related genes BCL2 (Bcl-2), FAS, Caspase-3, BAX and the new member BCL2L12, cloned by our group, along with treatment of HL-60 leukemia cells with etoposide. The kinetics of apoptosis induction and cell toxicity was evaluated by DNA laddering and MTT method, respectively. The mRNA expression levels of the genes were analyzed by RT-PCR using gene-specific primers. Beta-actin was used as a control gene. An important downregulation of BCL2L12 was observed at 4 h of drug treatment, whereas BAX was upregulated at the same time point. No alteration in the expression pattern of the other apoptosis-related genes was detected. Since, the main anticarcinogenic effect of etoposide is due to the induction of apoptosis, these changes observed in the mRNA expression levels of the genes may be an underlying mechanism.
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PMID:Alterations in mRNA expression of apoptosis-related genes BCL2, BAX, FAS, caspase-3, and the novel member BCL2L12 after treatment of human leukemic cell line HL60 with the antineoplastic agent etoposide. 1738 50

In search for innovative therapeutic agents for children neuroblastoma, the oxygen therapy could be considered an alternative anti-tumoral treatment. Given the physiochemical properties of O(2/3) gas mixture including fairly low aqueous solubility and spreading, and the interesting perspective of hyperoxia, we analyzed the inhibitory effect of O(2/3) treatment on two human neuroblastoma cell lines (SK-N-SH and SK-N-DZ). In this study, we demonstrated that O(2/3) treatment was able to induce cell growth inhibition and cell cycle perturbation in both cell lines. We observed an arrest at G(2) phase, accompanied by an alteration in the expression and localization of cyclin B1/cdk1 complex and a reduction in its activity in SK-N-SH cells. This reduction was consistent with the increase in both Wee1 and chk1 protein levels. On the contrary, O(2/3) induced apoptosis in SK-N-DZ cells via caspase 3 activation and Poly ADP-ribose polymerase-1 (PARP) cleavage, associated with an increase in the pro-apoptotic Bax protein. Consequently, we considered the possibility of improving the responsiveness to chemotherapeutic agents such as Cisplatin, Etoposide, and Gemcitabine in combination with O(2/3) treatment. The combined treatments produced a stronger cell inhibitory effect than Cisplatin and Etoposide used alone in SK-N-SH cells. On the contrary, the combination data were not significantly different from O(2/3) treatment alone in SK-N-DZ cells, thus suggesting that the obtained changes in cell growth inhibition were due to the effect of O(2/3) alone.
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PMID:O(2/3) exposure inhibits cell progression affecting cyclin B1/cdk1 activity in SK-N-SH while induces apoptosis in SK-N-DZ neuroblastoma cells. 1747 75

The major obstacle to successful treatment of gastric cancer is chemotherapy resistance. Our study was designed to investigate the role of phosphoinositide 3-kinase (PI3K)/Akt pathway in the development of chemoresistance in gastric cancer. In the present study, elevated Akt expression and Akt phosphorylation (Ser 473), as well as decreased PTEN expression were observed in 28 cases of gastric cancer tissues. Etoposide and doxorubicin stimulated Akt and PI3K activities in 2 gastric cancer cell lines (BGC-823 and SGC-7901), and the activities were concentration and time-dependent. Up-regulation of PTEN expression in BGC-823 cells by PEAK8-PTEN transient transfection obviously decreased the basal and anticancer drugs induced Akt activities, then sensitized BGC-823 cells to etoposide and doxorubicin. Pretreatment of BGC-823 and SGC-7901 cells with wortmannin, a PI3K inhibitor, attenuated cells's resistance to etoposide and doxorubicin. In addition, pretreatment of wortmannin blocked etoposide and doxorubicin induced IkappaB-alpha degradation, NFkappaB activation, phosphorylation of Akt, MDM-2 and forkhead transcription factors. Wortmannin pretreatment also promoted the accumulation of p27/Kip, but inhibited the Mcl-1 expression. Furthermore, wortmannin promoted etoposide and doxorubicin induced caspase-3, caspase-9 activation and poly ADP-ribose polymerase cleavage. Taken together, the observations indicate the PI3K/Akt pathway plays an important role in the chemoresistance of gastric cancer cells. A new strategy for combined chemotherapy of gastric cancer should be designed to more specifically block PI3K/Akt pathway and then decrease the amount of resistant cells.
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PMID:Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. 1793 37

Glycogen synthase kinase-3beta (GSK3beta) controls the survival of osteoblasts during bone development through Wnt canonical signaling. GSK3beta is a key factor for osteoblastogenesis, but relatively less is known regarding its role in osteoblast apoptosis. Genotoxic stress induced by etoposide promoted apoptotic signaling by GSK3beta activation in C3H10T1/2 cells, a mouse mesenchymal cell line. Etoposide led to the time-dependent activation of GSK3beta and caspase-3, which resulted in PARP cleavage. LiCl (a specific inhibitor) and siRNA (gene knock-down) of GSK3beta prevented the effects of etoposide on apoptosis. Staurosporine also induced apoptosis in C3H10T1/2 cells, but LiCl could not rescue. Bcl-2 was decreased in the cells by exposure to etoposide. LiCl completely recovered Bcl-2 expression as shown by both the mRNA and the protein expression levels. In conclusion, etoposide-induced apoptosis in C3H10T1/2 cells is mediated by GSK3beta, which leads to caspase-3 activation via decrease in Bcl-2 expression.
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PMID:Glycogen synthase kinase-3beta regulates etoposide-induced apoptosis via Bcl-2 mediated caspase-3 activation in C3H10T1/2 cells. 1940 26

Dysregulated apoptosis is a critical failure associated with prominent degenerative diseases including osteoporosis. In bone, estrogen deficiency has been associated with accelerated osteoblast apoptosis and susceptibility to osteoporotic fractures. Hormone therapy continues to be an effective option for preventing osteoporosis and bone fractures. Induction of apoptosis in G-292 human osteoblastic cells by exposure to etoposide or the inflammatory cytokine TNF-alpha promoted acute caspase-3/7 activity and this increased activity was inhibited by pretreatment with estradiol. Etoposide also increased the expression of a battery of apoptosis-promoting genes and this expression was also inhibited by estradiol. Among the apoptotic genes whose expression was inhibited by estradiol was ITPR1, which encodes the type 1 InsP3R. InsP3Rs are intracellular calcium channels and key proapoptotic mediators. Estradiol via estrogen receptor beta1 suppresses ITPR1 gene transcription in G-292 cells. These analyses suggest that an underlying basis of the beneficial activity of estrogens in combating osteoporosis may involve the prevention of apoptosis in osteoblasts and that a key event in this process is the repression of apoptotic gene expression and inhibition of caspase-3/7.
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PMID:Estrogen regulation of apoptosis in osteoblasts. 1942 47

Cytotoxicity and apoptosis induced by etoposide were studied during 72 hr in human melanoma cells. Etoposide initiated DNA-damage signaling via ATM kinase and activated p53 pathway and caspase-2. In response to treatment with etoposide, mitochondria of melanoma cells first increased their abundance and activity, and at later treatment intervals their dynamic behavior and functions became suppressed. Observed mitochondrial perturbation was not preceded by membrane potential loss but cytochrome c release was observed together with a rise in caspase-9 and caspase-3 activities. The pharmacological inhibition of relevant induced targets proved the importance of ATM and caspase-2 in etoposide-mediated cytotoxicity and apoptosis.
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PMID:Cytotoxicity and mitochondrial apoptosis induced by etoposide in melanoma cells. 1948 5

In this report, we reveal that etoposide inhibits the proliferation of SK-N-AS neuroblastoma cancer cells and promotes protein kinase Cdelta (PKCdelta)- and caspase-dependent apoptosis. Etoposide induces the caspase-3-dependent cleavage of PKCdelta to its active p40 fragment, and active PKCdelta triggers the processing of caspase-3 by a positive-feedback mechanism. Treatment of cells with the caspase-3-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone or caspase-3-specific small interacting RNA (siRNA) prevented the etoposide-induced activation of caspase-8 and inhibited apoptosis. The silencing of the caspase-2 or caspase-8 genes using siRNAs did not affect the etoposide-induced processing of caspase-3, indicating that these caspases lie downstream of caspase-3 in this signaling pathway. Furthermore, the etoposide-induced processing of caspase-2 required the expression of caspase-8, and the etoposide-mediated processing of caspase-8 required the expression of caspase-2, indicating that these two caspases activate each other after etoposide treatment. We also observed that etoposide-mediated apoptosis was decreased by treating the cells with the caspase-6-specific inhibitor benzyloxycarbonyl-Val-Glu(OMe)-Ile-Asp-(OMe)-fluoromethyl ketone and that caspase-6 was activated by a caspase-8-dependent mechanism. Finally, we show that rottlerin blocks etoposide-induced apoptosis by inhibiting the PKCdelta-mediated activation of caspase-3 and by degrading caspase-2, which prevents caspase-8 activation. Our results add important insights into how etoposide mediates apoptotic signaling and how targeting these pathways may lead to the development of novel therapeutics for the treatment of neuroblastomas.
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PMID:Etoposide induces protein kinase Cdelta- and caspase-3-dependent apoptosis in neuroblastoma cancer cells. 1954 63


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