Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of Ca2+ on the effects of capsaicin on human leukemia HL-60 cells in vitro and the molecular mechanisms of capsaicin-induced apoptosis were investigated. The flow cytometric analysis indicated that capsaicin decreased the percentage of viable HL-60 cells, via the induction of G0/G1-phase cell cycle arrest and apoptosis. Capsaicin-induced G0/G1-phase arrest involved the suppression of CDK2 and the cyclin E complex, which are check-point enzymes for cells moving from G0/G1- to S-phase. Capsaicin-induced apoptosis was associated with the elevation of intracellular reactive oxygen species and Ca2+ production, decreased the levels of mitochondrial membrane potential, promoted cytochrome c release and increased the activation of caspase-3. An intracellular Ca2+ chelator (BAPTA) significantly inhibited capsaicin-induced apoptosis. Capsaicin-induced apoptosis was time-and dose-dependent. These results suggest that the capsaicin-induced apoptosis of HL-60 cells may result from the activation of caspase-3 and the intracellular Ca2+ release pathway.
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PMID:Involvement of Bax, Bcl-2, Ca2+ and caspase-3 in capsaicin-induced apoptosis of human leukemia HL-60 cells. 1682 31

Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of cyclin A1 action are incompletely understood. Here, we show that cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by cyclin A1/CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells.
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PMID:DNA damage response involves modulation of Ku70 and Rb functions by cyclin A1 in leukemia cells. 1745 44

Inhibition of cyclin-dependent kinases (CDKs) is a novel strategy in the therapy of human malignancies. The pharmacological CDK inhibitors representing a few distinct classes of compounds exert different target specificity. Considering the fact that dividing and quiescent cells differ in their CDK activity and in the pattern of their expression, one might expect that anti-proliferative efficiency of the pharmacological CDK inhibitors would depend on the mitotic index of treated cells. The present article shows that olomoucine (OLO), a weak CDK2 inhibitor has new, unexpected activity. At concentrations up to 100 microM OLO did not inhibit proliferation of normal human cells, but arrested growth of human HL-60 leukemia cells. The anti-proliferative effect of OLO was clearly weaker than that of roscovitine (ROSC). Surprisingly, OLO at low doses strongly up-regulated a cellular protein with approximately 65 kDa in normal, but not in immortalized and cancer cells. By mass spectrometric analysis CLIMP-63, a cytoskeleton-linking membrane protein was identified as the major component of the up-regulated protein band. These results were subsequently confirmed by immunoblotting. Further experiments revealed that OLO, but not ROSC, strongly up-regulates CLIMP-63 in a dose- and time-dependent manner solely in senescent cells.
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PMID:A new, unexpected action of olomoucine, a CDK inhibitor, on normal human cells: up-regulation of CLIMP-63, a cytoskeleton-linking membrane protein. 1797 94

Human T-cell leukemia virus type-1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATL/L), a fatal lymphoproliferative disorder, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic progressive disease of the central nervous system after a long period of latent infection. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral oncoprotein Tax plays a crucial role in these processes through the regulation of several pathways including NF-kappaB and the cell cycle pathways. The observation that NF-kappaB, which is strongly induced by Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-1 by regulating the expression of various genes involved in cell cycle regulation and inhibition of apoptosis provides a possible molecular target for these infected cells. To develop potential new therapeutic strategies for HTLV-1 infected cells, in this present study, we initially screened a battery of NF-kappaB and CDK inhibitors (total of 35 compounds) to examine their effects on the growth and survival of infected T-cell lines. Two drugs namely BMS-345541 and Purvalanol A exhibited higher levels of growth inhibition and apoptosis in infected cell as compared to uninfected cells. BMS-345541 inhibited IKKbeta kinase activity from HTLV-1 infected cells with an IC50 (the 50% of inhibitory concentration) value of 50 nM compared to 500 nM from control cells as measured by in vitro kinase assays. The effects of Purvalanol A were associated with suppression of CDK2/cyclin E complex activity as previously shown by us. Combination of both BMS-345541 and Purvalanol A showed a reduced level of HTLV-1 p19 Gag production in cell culture. The apparent apoptosis in these infected cells were associated with increased caspase-3 activity and PARP cleavage. The potent and selective apoptotic effects of these drugs suggest that both BMS-345541 and Purvalanol A, which target both NF-kappaB and CDK complex and the G1/S border, might be promising new agents in the treatment of these infected patients.
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PMID:Two specific drugs, BMS-345541 and purvalanol A induce apoptosis of HTLV-1 infected cells through inhibition of the NF-kappaB and cell cycle pathways. 1854 67

Pectenotoxin-2 (PTX-2) is a natural compound from marine sponges and has been known to inhibit cytokinesis through the depolymerization of actin filaments. To investigate the role of actin dysfunction by PTX-2 in human leukemia cells, we analyzed the effect of PTX-2 on the cell cycle and apoptosis. Cell cycle analysis showed that the depolymerization of actin with PTX-2 induces G2/M phase arrest at 12 h and endoreduplication at 24 h. Analysis of the cell cycle regulatory proteins demonstrated that PTX-2 increases phosphorylation of cdc25c and decreases the protein levels of cdc2 and cyclin B1. The M phase specific marker protein, phospho-histone 3, was also increased by PTX-2. Furthermore, p21 and CDK2, which are associated with the induction of endoreduplication, were also upregulated. PTX-2 also inhibited the growth of leukemia cells and caused a marked increase in apoptosis, as characterized by annexin-V+ cells and caspase-3 activity. Interestingly, we found that induction of G2/M phase arrest, endoreduplication, and apoptosis by PTX-2 is regulated by the extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) pathway. Inhibitors of ERK and JNK more increased the phosphorylation of cdc25c expression at G2/M arrest stages, and decreased p21 and CDK2 expression at endoreduplication stages and Bax expression at apoptotic stages in the presence of PTX-2. These molecular mechanisms provide that PTX-2 induces G2/M phase arrest, endoreduplication, and apoptosis through the ERK and JNK signal pathway via actin depolymerization.
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PMID:Induction of G2/M arrest, endoreduplication, and apoptosis by actin depolymerization agent pextenotoxin-2 in human leukemia cells, involving activation of ERK and JNK. 1857 Nov 48

Results of a number of epidemiological and experimental studies indicate that polyphenols (e.g. resveratrol (RES), epicatechins etc.), antioxidant agents and abundant micronutrients in our food could have strong anti-mitotic as well as pro-apoptotic effects. In this study we raised the question whether roscovitine (ROSC), an inhibitor of cyclin-dependent kinases (CDKs) with increased selectivity towards CDK2, could be able to affect human leukemia HL-60 cells in which the p53 gene is inactivated and whether ROSC-induced effects could be additionally modulated by compounds of natural origin, especially by polyphenols e.g. RES. Exposure of HL-60 cells to ROSC for 24 h inhibited their proliferation. Flow cytometric analyses revealed that unlike MCF-7 cells, HL-60 cells were arrested in G(1) upon ROSC treatment. Furthermore, ROSC also induced apoptosis in HL-60 cells. After treatment with 40 microM ROSC for 24 h the frequency of hypoploid cells representing cells undergoing apoptosis reached approximately 50%. In the next step the action of RES alone or in combination with ROSC was examined. Interestingly, synergistic effects were observed after combined treatment for 24 h and sequential post-incubation for 48 h in the presence of RES. Such combined treatment resulted in a marked reduction of the frequency of the S- and G(2)/M-phase cells and simultaneously increased the G(1) cell population up to 80% at a fourfold lower ROSC dose. Further analyses revealed that the combined treatment strongly activated caspase-3. These results clearly evidence that RES strongly potentiates ROSC-induced apoptosis.
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PMID:Action of resveratrol alone or in combination with roscovitine, a CDK inhibitor, on cell cycle progression in human HL-60 leukemia cells. 1876 29

Previously, we demonstrated that magnolol isolated from the bark of Magnolia officinalis has anticancer activity in colon, hepatoma, and leukemia cell lines. In this study, we show that magnolol concentration dependently (0-40 microM) decreased the cell number in a cultured human glioblastoma cancer cell line (U373) and arrested the cells at the G0/G1 phase of the cell cycle. Magnolol treatment decreased the protein levels of cyclins A and D1 and increased p21/Cip1, but not cyclins B and D3, cyclin-dependent kinase (CDK)2, CDK4, CDC25C, Weel, p27/Kip1, and p53. The CDK2-p21/Cip1 complex was increased, and the CDK2 kinase activity was decreased in the magnolol-treated U373. Pretreatment of U373 with p21/Cip1 specific antisense oligodeoxynucleotide prevented the magnolol-induced increase of p21/Cip1 protein levels and the decrease of DNA synthesis. Magnolol at a concentration of 100 microM induced DNA fragmentation in U373. Our findings suggest the potential applications of magnolol in the treatment of human brain cancers.
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PMID:Magnolol inhibits human glioblastoma cell proliferation through upregulation of p21/Cip1. 1964 6

A series of functionalized isoindigos structurally related to meisoindigo (1-methylisoindigo), a therapeutic agent used for the treatment of a form of leukemia, were synthesized and evaluated for antiproliferative activities on a panel of human cancer cells. Two promising compounds (1-phenpropylisoindigo and 1-(p-methoxy-phenethyl)-isoindigo) that were more potent than meisoindigo and comparable to 6-bromoindirubin-3'-oxime on leukemic K562 and liver HuH7 cells were identified. Structure-activity relationships showed the importance of keeping one of the lactam NH in an unsubstituted state. Substitution of the other lactam NH with aryl or arylalkyl side chains retained or improved activity in most instances. An intact exocyclic double bond was also essential, possibly to maintain planarity and rigidity of the isoindigo scaffold. None of the compounds were found to inhibit CDK2 in an in vitro assay, in spite of reports linking the antiproliferative activities of meisoindigo and other isoindigos to CDK2 inhibition. Hence, these functionalized isoindigos disrupted cell growth and proliferation by other mechanistic pathways that did not involve CDK2 inhibition.
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PMID:Synthesis and evaluation of functionalized isoindigos as antiproliferative agents. 1978 49

Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the principal mechanisms by which tumor cells escape the cell death induced by chemotherapeutic agents. In our previous study, we demonstrated that KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a synthetic histone deacetylase inhibitor, effectively inhibited the growth of several human cancer cell lines. In this study, we attempted to determine whether KBH-A42 was also capable of inhibiting the growth of multidrug-resistant cells. Doxorubicin dose-dependently inhibited the growth of P-gp-negative K562 human leukemia cells, but did not show substantial inhibition on the growth of P-gp-positive K562/ADR cells even at 10 microM, the highest concentration of KBH-A42 used, which increased the acetylation of histones in these leukemia cells, dose-dependently and effectively inhibited the cell growth, regardless of the presence of P-gp in the cells. KBH-A42 mediated G0/G1 cell cycle arrest, probably as the result of the down-regulation of CDK2, CDK4 and CDK6 and the up-regulation of p21WAF1. When the expression of p21WAF1 was ablated by a specific siRNA, the inhibition of cell growth by KBH-A42 was partly reduced in both cell lines. In addition to the cell cycle arrest, KBH-A42 also induced apoptosis in these cells, which was accompanied by the activation of caspases, including caspase-9, caspase-8 and caspase-3. The pan-caspase inhibitor, Z-VAD-fmk, partially blocked the cell death induced by KBH-A42. These results indicate that KBH-A42 induces cell cycle arrest and apoptosis via the up-regulation of p21WAF1 and caspase activation, respectively, regardless of the presence of P-gp in the leukemia cells.
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PMID:KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein. 2012 23

G-rich oligonucleotides (GROs) belong to a novel class of phosphodiester oligonucleotides. They can form G-tetramer structure which contributes to cell cycle arrest and growth inhibitory effects by non-antisense pathway. This study was aimed to investigate the biological effects of GRO-26B on leukemia cell lines. Cell proliferation of different cell lines were detected by using MTT method and trypan blue incorporation assay. Alteration of cell cycle was analyzed by using flow cytometry. Apoptosis was detected by using Annexin V/PI kit. Western blot was used to detect the expression level of cyclins and CDKs. Morphological features of GRO-26B-treated cells was observed by light microscopy and transmission electron microscopy (TEM). The results showed that GRO-26B could inhibit the proliferation of AML cell lines, such as U937 and NB4 cells in a dose-dependent manner. GRO-26B induced the cell cycle to be arrested at S phase in time-dependent manner, which was associated with the alteration of cyclin A, cyclin B, CDC2 and CDK2. The morphology of cells treated by GRO-26B also showed a distinct change as compared to the untreated cells. It is concluded that GRO-26B can inhibit AML cell proliferation, which is partially associated to cell cycle arrest at S phase. The S phase arrest is related to cyclins/CDKs. The regulation mechanism of cell cycle and proliferation is complicated. All of the above-mentioned phenomena need to be studied in the future.
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PMID:[Inhibition of leukemia cell proliferation by G-rich oligonucleotides]. 2013 12


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