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)

We investigated endocytosis activity, uptake of miltefosine (hexadecylphosphocholine), phospholipid and cholesterol content, the cell cycle, and apoptosis in 13 tumor cell lines (MCF7, MCF7/ADR, KB-3-1, KB-8-5, KB-C1, HeLa, HeLa-MDR1-G185, HeLa-MDR1-V185, CCRF/CEM, CCRF/VCR1000, CCRF/ADR5000, HL-60, HL-60/AR) with different sensitivities to treatment with the antitumor phospholipid analogues miltefosine and D-21266 (octadecyl-(N,N-dimethyl-piperidino-4-yl)-phosphate). In this panel of cell lines, MDR1 (multidrug resistance gene 1)- and MRP1 (multidrug resistance-associated protein)-expressing cells were found to be slightly more resistant to both compounds than sensitive parental cells. No correlation was found between resistance to miltefosine and endocytosis, intracellular concentration of miltefosine, the phospholipid and cholesterol content, induction of apoptosis, or cell cycle alterations in all the cell lines tested. Wild-type p53 containing WMN Burkitt's lymphoma cells and wild type p53-deficient CA46 exhibited similar sensitivities to miltefosine. The low percentage of apoptosis induced in MCF7 cells lacking caspase 3 indicated that caspase 3 seems to play an essential role in miltefosine-induced apoptosis.
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PMID:Effects of miltefosine on various biochemical parameters in a panel of tumor cell lines with different sensitivities. 1155 22

In the present study, we outlined the part of the molecule mediating the prominent pro-apoptotic effect of the Michael adduct of ascorbic acid with p-chloro-nitrostyrene, a new synthetic phosphatase inhibitor. The nitrostyrene (NS) moiety was identified as the structure essential for apoptosis induction. NS and its ascorbic acid adducts displayed LC(50) values of 10-25 microM with no significant reduction of potency in okadaic acid resistant cells overexpressing the MDR1 P-glycoprotein. Induction of apoptosis by NS derivatives and the protein phosphatase 2A inhibitor cantharidic acid was proven by the analysis of caspase-3 activation and subsequent fragmentation of DNA. Further structure activity analysis revealed the necessity of the nitro group at the beta-position of the side chain. The pro-apoptotic potential of adducts of NS with pyrimidine- or pyridine-derivatives varied between NS and a progressive reduction in potency up to a nearly complete loss of cytotoxicity. Substitutions at the benzene core of NS suggested a prominent enhancement of toxicity only by substitutions at the 2- or 3-position. Heterocyclic aromatics can substitute for the benzene ring of NS albeit with a 2-3-fold reduced potency. In conclusion, nitrostyrene was identified as the core structure mediating the pro-apoptotic effect of a new synthetic phosphatase inhibitor. Further studies defined a nitrovinyl side chain attached to an aromatic ring as the pharmacophore structure of a new group of pro-apoptotic agents. These observations present the basis for the development of a new group of anticancer drugs.
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PMID:Structure activity analysis of the pro-apoptotic, antitumor effect of nitrostyrene adducts and related compounds. 1256 88

We have evaluated the effects of monensin liposomes on drug resistance reversal, induction of apoptosis and expression of multidrug resistance (MDR) genes in a doxorubicin-resistant human breast tumour (MCF-7/dox) cell line. Monensin liposomes were prepared by the pH-gradient method. MCF-7/dox cells were treated with various anticancer drugs (doxorubicin, paclitaxel and etoposide) alone and in combination with monensin liposomes. The cytotoxicity was assessed using the crystal violet dye uptake method. The induction of apoptosis in MCF-7/dox cells was assessed by established techniques such as TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labelling) staining and caspase-3 assay. The effect of monensin liposomes on doxorubicin accumulation in MCF-7/dox cells was monitored by fluorescent microscopy. Finally, the expression of MDR genes (MDR1 and MRP1) in MCF-7/dox cells following the exposure to doxorubicin alone and in combination with monensin liposomes was evaluated by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Our results indicated that monensin liposomes overcame drug resistance in MCF-7/dox cells to doxorubicin, etoposide and paclitaxel by 16.5-, 5.6- and 2.8-times, respectively. The combination of doxorubicin (2.5 microg mL(-1)) with monensin liposomes (20 x 10(-8)M) induced apoptosis in approximately 40% cells, whereas doxorubicin (2.5 microg mL(-1)) or monensin liposomes (20 x 10(-8)M) alone produced minimal apoptosis (<10%) in MCF-7/dox cells. Fluorescent microscopy revealed that monensin liposomes increased the accumulation of doxorubicin in MCF-7/dox cells. RT-PCR studies demonstrated that the expression of MDR1 and MRP1 was increased by 33 and 57%, respectively, in MCF-7/dox cells following treatment with doxorubicin (2.5 microg mL(-1)) for 72 h as compared with control MCF-7/dox cells. Furthermore, the levels of MDR1 and MRP1 in MCF-7/dox cells exposed to both doxorubicin and monensin liposomes showed a modest decrease as compared with MCF-7/dox cells treated with doxorubicin alone. In conclusion, the delivery of monensin via liposomes provided an opportunity to overcome drug resistance.
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PMID:Effects of monensin liposomes on the cytotoxicity, apoptosis and expression of multidrug resistance genes in doxorubicin-resistant human breast tumour (MCF-7/dox) cell-line. 1523 69

The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (NAs) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside)-induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5'-nucleotidases (50-100%). The ratio 5'-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5'-nucleotidase/deoxycytidine kinase ratio might be an important factor in predicting resistance to NAs. Implications of this finding for combining anthracyclines or vinca alkaloids with NAs toward leukemic cells are discussed.
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PMID:Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells. 1524 Jan 22

Extensive researches have revealed that arsenical can exert anti-tumor efficacy against several kinds of cancers including leukemia. Though, little is known about the effects of arsenical on leukemia resistant to chemotherapy, emerging as a serious clinical problem. In this study, we tested arsenic trioxide (As(2)O(3))-induced apoptosis in K562/ADM multidrug-resistant leukemic cells and investigated its possible mechanisms. Using microscopy, flow cytometry (FCM) and DNA electrophoresis, we found that As(2)O(3) could induce the cells to undergo G2/M phase arrest and apoptosis. Further, it was shown that the levels of FAS and P53 proteins increased and P-glycoprotein (P-gp) decreased upon drug action by employing FCM. Reverse transcription polymerase chain reaction (RT-PCR) detected increased mRNA product of FAS and caspase-3 genes and reduced MDR1 mRNA. CASPASE-3 activity was also enhanced after As(2)O(3) treatment. However, the expression of BCL-2 protein was not affected by the drug. Taken together, As(2)O(3) is able to reverse the apoptosis resistance in drug-resistant K562/ADM cells by modulating expression or activity of key factors associated with apoptosis induction.
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PMID:Arsenic trioxide overcomes apoptosis inhibition in K562/ADM cells by regulating vital components in apoptotic pathway. 1597 94

We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrug-resistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60NP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the pre-mitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 over-expression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo.
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PMID:Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. 1628 Oct 67

Permeability-glycoprotein (Pgp) positive cells are known to be encoded by the multidrug-resistance gene (MDR1), and characterized by a reduced ability to accumulate drugs. The vinblastin-resistant, Pgp positive CEM-VLB 1000 and its wild type (Pgp-negative and vinblastin-sensitive) counterpart CEM-T4 human leukemia cells, when treated with the alkaloid sanguinarine, were both found to undergo apoptosis at concentrations of 1.5 microg/ml and oncosis/blister cell death (BCD) at concentrations of 12.5 microg/ml. The aim of this study was to assess the ability of sanguinarine to overcome Pgp-mediated multidrug-resistance (MDR), and also to characterize the cell death processes of apoptosis and oncosis (or bimodal cell death) induced by sanguinarine in MDR cells. The cell death processes of apoptosis and oncosis in CEM-VLB 1000 and CEM-T4 cell lines were found to be qualitatively similar when assessed by light microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling, annexin-V-binding, trypan blue exclusion and western blot analysis. Western blotting revealed an increase in the Bax/Bcl-2 ratio and activation of caspase-3 in apoptosis but not oncosis in both cell lines. The Pgp-positive CEM-VLB 1000 cells and their wild type CEM-T4 cells were both equally sensitive to sanguinarine. Thus, sanguinarine may overcome the phenomenon of Pgp-mediated MDR by inducing apoptosis through increasing the Bax/Bcl-2 ratio and activating caspase-3, and oncosis, which involved neither.
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PMID:Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells. 1673 6

The new glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines, i.e. CEM-VBL10, CEM-VBL100, and U-2 OS/DX580. The mechanism of cell death triggered by NBDHEX has been deeply investigated in leukemia cell lines. Kinetic data indicate a similar NBDHEX membrane permeability between multidrug resistance cells and their sensitive counterpart revealing that NBDHEX is not a substrate of the P-glycoprotein export pump. Unexpectedly, this molecule promotes a caspase-dependent apoptosis that is unusual in the P-glycoprotein-overexpressing cells. The primary event of the apoptotic pathway is the dissociation of glutathione S-transferase P1-1 from the complex with c-Jun N-terminal kinase. Interestingly, leukemia MDR1-expressing cells show lower LC50 values and a higher degree of apoptosis and caspase-3 activity than their drug-sensitive counterparts. The increased susceptibility of the multidrug resistance cells toward the NBDHEX action may be related to a lower content of glutathione S-transferase P1-1. Given the low toxicity of NBDHEX in vivo, this compound may represent an attractive basis for the selective treatment of MDR1 P-glycoprotein-positive tumors.
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PMID:A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells. 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells. 1676 21

Two 4-methylideneisoxazolidin-5-ones (4a,b), which are alpha-methylidene-gamma-lactones containing a nitrogen atom in the lactone ring, were synthesized. Their cytotoxic properties were evaluated against promyelocytic leukemia HL-60 cells. Both 4a and 4b exhibited relatively high cytotoxic activity with an IC(50) of 4.1 and 5.4 microM, respectively. Caspase-3 activity assay revealed that both isoxazolidinones (4) were able to induce apoptosis process in time- and concentration-dependent manner. Using multiplex PCR analysis, it was observed that 4 caused distinct inhibition of BCL-2 gene expression. Expression of BAX, a pro-apoptotic gene remained unchanged. It was also found that 4a,b did not induce the expression of MDR1 and MRP1 genes, related to multidrug resistance. In addition, cytotoxicity data obtained for drug-sensitive and drug-resistant HL-60 ADR cells revealed that the investigated compounds were poor substrates for transport by MRP1 efflux pump, suggesting that they might be useful for treating drug-resistant tumors. Furthermore, antimicrobial properties of 4a,b were evaluated. They showed significant activity against fungi Candida albicans, but only a weak activity against all tested Gram-positive and Gram-negative bacterial strains.
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PMID:Synthesis and biological evaluation of 4-methylideneisoxazolidin-5-ones--a new class of highly cytotoxic alpha-methylidene-gamma-lactones. 1706 34

In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein-mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype. Experiments were done using MDR-positive and parental cell lines at basal conditions and after exposure to 10 or 50 micromol/L celecoxib. We found that 10 micromol/L celecoxib reduced P-glycoprotein, Bcl-x(L), and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells. This causes the activation of caspase-3 and increases the number of cells going into apoptosis. No effect was shown on parental drug-sensitive or on MDR-positive hepatocellular carcinoma cells after transfection with MDR1 small interfering RNA. Interestingly, although inhibiting COX-2 activity, 50 micromol/L celecoxib weakly increased the expression of COX-2 and P-glycoprotein and did not alter Bcl-x(L) and Bcl-2 expression. In conclusion, these results show that relatively low concentrations of celecoxib induce cell apoptosis in MDR cell lines. This effect is mediated by P-glycoprotein and suggests that the efficacy of celecoxib in the treatment of different types of cancer may depend on celecoxib concentration and P-glycoprotein expression.
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PMID:P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines. 1751 Apr 21


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