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)

Monensin, an Na(+) ionophore, regulates many cellular functions including apoptosis. However, there has been no report about the antitumoral effect of monensin on acute myelogenous leukemia (AML). Here, we investigated the antiproliferative effect of monensin on AML cells in vitro and in vivo. Monensin efficiently inhibited the proliferation of all of 10 AML cell lines, with IC(50) of about 0.5 microM. DNA flow cytometric analysis indicated that monensin induced a G(1) and/or a G(2)-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of monensin on cell cycle-related proteins in HL-60 cells. The levels of CDK6, cyclin D1 and cyclin A were decreased. In addition, monensin not only increased the p27 level but also enhanced its binding with CDK2. Furthermore, the activities of CDK2- and CDK6-associated kinases reduced by monensin were associated with hypophosphorylation of Rb protein. Monensin also induced apoptosis in AML cells including HL-60 cells. The apoptotic process of HL-60 cells was associated with changes in Bax, caspase-3, caspase-8 and mitochondria transmembrane potential (Deltapsi(m)). In particular, monensin (i.p. at a dose of 8 mg/kg thrice weekly) significantly reduced the tumor size of BALB/c mice that were inoculated s.c. with its derived cell line, WEHI-3BD cells (69% growth inhibition relative to control group; p < 0.05). Tumors from monensin-treated mice exhibited increased apoptosis, and these tumor were immunohistochemically more stained with Bax, Fas and p53 antibodies than control tumors. In conclusion, this is the first report that monensin potently inhibits the proliferation of AML cells.
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PMID:Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis. 1220 73

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we demonstrate that monensin inhibited the proliferation of solid tumor cells with IC50 of about 2.5 micro M. Monensin induced a G1 or a G2-M phase arrest in these cells. When we examined the effects of this drug on SNU-C1 cells, monensin decreased the levels of CDK2, CDK4, CDK6, cyclin D1 and cyclin A proteins. While p27 was increased by monensin, p21 was not. In addition, monensin markedly enhanced the binding of p27 with CDK2, CDK4 and CDK6. Furthermore, the activities of CDK2-, CDK4- and CDK6-associated kinase were reduced in association with hypophosphorylation of Rb protein. Monensin also induced apoptosis in solid tumor cells. Apoptotic process of SNU-C1 cells was associated with the changes of Bax, caspase-3 and mitochondria transmembrane potential (deltapsim). Taken together, these results demonstrated for the first time that monensin inhibited the growth of solid tumor cells, especially SNU-C1 cells, via cell cycle arrest and apoptosis.
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PMID:Monensin-mediated growth inhibition of SNU-C1 colon cancer cells via cell cycle arrest and apoptosis. 1252 37

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we demonstrate that monensin inhibited the proliferation of renal cell carcinoma cells with IC50 of about 2.5 micro M. Monensin induced a G1 or a G2-M phase arrest in these cells. When we examined the effects of this drug on ACHN cells, monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A and cyclin B1 proteins. p21 and p27 proteins were increased by monensin. In addition, monensin markedly enhanced the binding of p21 with CDK2 and the binding of p27 with CDK6. Furthermore, the activities of CDK2- and CDK6-associated kinase were reduced in association with hypophosphorylation of Rb protein. Monensin also induced the apoptosis in several renal cell carcinoma cells. Apoptotic process of Caki-2 cells was associated with the changes of Bcl-2, Bcl-XL, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (DeltaPsim) loss. Taken together, these results demonstrate for the first time that monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
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PMID:Monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis. 1263 79

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
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PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

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