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)

Drug resistance continues to be a serious problem in cancer therapy. We investigated whether indomethacin, which inhibited cyclooxygenases, would overcome doxorubicin resistance in K562/ADR leukemia cells. Indomethacin at 10 muM increased the cytotoxicity of doxorubicin, as well as vincristine in K562/ADR. Both multi-drug resistant protein1 (MRP1) and P-glycoprotein were overexpressed in K562/ADR cells when compared with K562 parent cells (K562/P). Expression of MRP1 mRNA and protein, but not P-glycoprotein, was significantly decreased in K562/ADR cells after indomethacin treatment. Indomethacin treatment increased 5(6)-carboxyfluorescein diacetate (CFDA) efflux, as well as decreased accumulation in K562/ADR cells. The activity of the MRP1 promoter decreased after indomethacin treatment in Hela cells. These data strongly suggest that the cyclooxygenase inhibitor, indomethacin, increased the cytotoxicity of doxorubicin with decreasing expression of MRP1 through inhibition of MRP1 promoter activity.
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PMID:Indomethacin overcomes doxorubicin resistance with inhibiting multi-drug resistance protein 1 (MRP1). 1633 95

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR-ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-alpha treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR-ABL-independent mechanisms.
Leukemia 2006 Jun
PMID:Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach. 1659 11

2,4,6-Triiodophenol (Bobel-24, AM-24) was originally described as a nonsteroid antiinflammatory molecule. We have synthesized three derivatives of Bobel-24 (Bobel-4, Bobel-16, and Bobel-30) and tested their activities as putative antileukemic agents. We have found that Bobel-24 and Bobel-16 were dual inhibitors of cyclooxygenase and 5-lipoxygenase, whereas Bobel-4 and Bobel-30 were selective against 5-lipoxygenase. We have tested the antiproliferative activity of these compounds on a panel of cell lines derived from myeloid and lymphoid leukemias (K562, Raji, HL-60, and Molt4). The cytotoxic IC(50) in these cell lines ranged between 14 and 50 micromol/L, but it was higher for nontransformed cells such as 32D, NIH3T3, or human leukocytes. All compounds showed cytotoxic activity on all tested cell lines, accompanied by DNA synthesis inhibition and arrest in the G(0)/G(1) phase. Bobel-16, Bobel-4, and Bobel-24 induced a caspase-independent cell death in K562 and Raji cells, accompanied by chromatin condensation, cytochrome c release, and dissipation of mitochondrial membrane potential in a concentration-dependent manner and production of reactive oxygen species. As the proto-oncogene MYC is involved in mitochondrial biogenesis and survival of leukemia cells, we tested its effect on bobel activity. Bobel-24 induced down-regulation of MYC in K562 and, consistently, ectopic expression of MYC results in partial protection towards the cytotoxic effect of Bobel-24. In conclusion, Bobel derivatives induce a caspase- and Bcl-2-independent cell death in which mitochondrial permeabilization and MYC down-regulation are involved. Bobels may serve as prototypes for the development of new agents for the therapy of leukemia.
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PMID:Novel triiodophenol derivatives induce caspase-independent mitochondrial cell death in leukemia cells inhibited by Myc. 1673 48

Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cell leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release from mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small-interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria.
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PMID:Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. 1754 41

Previous screening of the pharmacological action of Gastrodia elata (GE) root (Orchidaceae) showed that methanol (MeOH) extracts have significant anti-inflammatory properties. The anti-inflammatory agents of GE, however, remain unclear. In this experiment, MeOH extracts of GE were fractionated with organic solvents for the anti-inflammatory activity-guided separation of GE. Eight phenolic compounds from the ether (EtOEt) and ethyl acetate (EtOAc) fractions were isolated by column chromatography: 4-hydroxybenzaldehyde (I), 4-hydroxybenzyl alcohol (II), benzyl alcohol (III), bis-(4-hydroxyphenyl) methane (IV), 4(4'-hydroxybenzyloxy)benzyl methylether (V), 4-hydroxy-3-methoxybenzyl alcohol (VI), 4-hydroxy-3-methoxybenzaldehyde (VII), and 4-hydroxy-3-methoxybenzoic acid (VIII). To investigate the anti-inflammatory and anti-oxidant activity of these compounds, their effects on carrageenan-induced paw edema, arachidonic acid (AA)-induced ear edema and analgesic activity in acetic acid (HAc)-induced writhing response were carried out in vivo; cyclooxygenase (COX) activity, reactive oxygen species (ROS) generation in rat basophilic leukemia (RBL 2H3) cells and 1,1-diphenyl-2-picryl-hydroazyl (DPPH) scavenging activity were determined in vitro. These phenolic compounds not only had anti-inflammatory and analgesic properties in vivo, but also inhibited COX activity and silica-induced ROS generation in a dose-dependent manner. Among these phenolic compounds, compound VII was the most potent anti-inflammatory and analgesic. Compound VII significantly inhibited silica-induced ROS generation and compound VI significantly increased DPPH radical scavenging activity. Compounds I, II and III significantly inhibited the activity of COX-I and II. These results indicate that phenolic compounds of GE are anti-inflammatory, which may be related to inhibition of COX activity and to anti-oxidant activity. Consideration of the structure-activity relationship of the phenolic derivatives from GE on the anti-inflammatory action revealed that both C-4 hydroxy and C-3 methoxy radicals of benzyl aldehyde play an important role in anti-inflammatory activities.
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PMID:Anti-inflammatory action of phenolic compounds from Gastrodia elata root. 1712 Nov 79

Dideoxypetrosynol A, a polyacetylene from the marine sponge Petrosia sp., is known to exhibit significant selective cytotoxic activity against several human cancer cell lines. In the present study, we investigated further possible mechanisms by which dideoxypetrosynol A exerts its anti-proliferative action in cultured human leukemia U937 cells. Exposure of U937 cells to dideoxypetrosynol A resulted in growth inhibition and induction of apoptosis as measured by hemocytometer counts, fluorescent microscopy, agarose gel electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with a dose-dependent up-regulation in pro-apoptotic Bax expression and activation of caspase-3 and caspase-9. Dideoxypetrosynol A decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E2 (PGE2) synthesis. Furthermore, dideoxypetrosynol A treatment markedly inhibited the activity of telomerase, and the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by dideoxypetrosynol A treatment in a dose-dependent fashion. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of dideoxypetrosynol A.
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PMID:Inhibition of cyclooxygenase-2 and telomerase activities in human leukemia cells by dideoxypetrosynol A, a polyacetylene from the marine sponge Petrosia sp. 1714 40

Curcumin (diferuloylmethane), is a natural product derived from the root of the plant Curcuma longa. For centuries, it has been used as a spice and as a herbal medicine in Chinese populations. Curcumin has been shown to inhibit cell proliferation, cell cycle arrest, cyclooxygenase (COX)-1 and -2 expression and apoptosis in several human cancer cell lines. The aim of this investigation was to clarify the mechanisms by which curcumin induced cytotoxicity and apoptosis in human leukemia HL-60 cells. The effects of curcumin on the levels of reactive oxygen species (ROS), Ca+2 production, cyclin E, cdc25c, wee1, Bcl-2, Bax, the changes of mitochondrial membrane potential (MMP), cytochrome c release and the activation of caspase-3 were also investigated in the HL-60 cells. Results of flow cytometry and DAPI staining assays indicated that curcumin induced cytotoxicity and apoptosis in the examined cells. The results from flow cytometry assay indicated that curcumin induced ROS and Ca+2 productions, decreased the levels of MMP and increased the activity of caspase-3, leading to cell apoptosis. Western blot assay also revealed that curcumin increased the levels of Bax and the release of cytochrome c, and decreased the levels of Bcl-2 in the examined cells. The inhibition of caspase-3 activation by z-VAD-fmk (broad-spectrum caspase inhibitor) completely blocked curcumin-induced apoptosis in HL-60 cells.
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PMID:Curcumin-induced cell cycle arrest and apoptosis in human acute promyelocytic leukemia HL-60 cells via MMP changes and caspase-3 activation. 1720 Nov 56

Aberrant arachidonic acid metabolism, especially altered cyclooxygenase and 5-lipoxygenase (LOX) activities, has been associated with chronic inflammation as well as carcinogenesis in human oral cavity tissues. Here, we examined the effect of Zyflamend, a product containing 10 concentrated herbal extracts, on development of 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced inflammation and oral squamous cell carcinoma (SCC). A hamster cheek pouch model was used in which 0.5% DMBA was applied topically onto the left cheek pouch of male Syrian golden hamsters either three times per week for 3 weeks (short term) or 6 weeks (long term). Zyflamend was then applied topically at one of three different doses (25, 50 and 100 microl) onto the left cheek pouch three times for 1 week (short-term study) or chronically for 18 weeks. Zyflamend significantly reduced infiltration of inflammatory cells, incidence of hyperplasia and dysplastic lesions, bromodeoxyuridine-labeling index as well as number of SCC in a concentration-dependent manner. Application of Zyflamend (100 microl) reduced formation of leukotriene B(4) (LTB(4)) by 50% compared with DMBA-treated tissues. The reduction of LTB(4) was concentration dependent. The effect of Zyflamend on inhibition of LTB(4) formation was further confirmed with in vitro cell-based assay. Adding LTB(4) to RBL-1 cells, a rat leukemia cell line expressing high levels of 5-LOX and LTA(4) hydrolase, partially blocked antiproliferative effect of Zyflamend. This study demonstrates that Zyflamend inhibited LTB(4) formation and modulated adverse histopathological changes in the DMBA-induced hamster cheek pouch model. The study suggests that Zyflamend might prevent oral carcinogenesis at the post-initiation stage.
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PMID:Zyflamend reduces LTB4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced hamster cheek pouch model. 1868 69

Despite its potential, use of trans-resveratrol as an anticancer drug is severely constrained because of its tendency to prolong gastric ulceration. We found that in addition to delaying ulcer healing, trans-resveratrol also aggravated acute gastric ulceration induced by the nonsteroidal anti-inflammatory drugs by reducing the synthesis of prostaglandin (PG) E(2) via a specific inhibition of cyclooxygenase (COX)-1 that also hampered angiogenesis. However, for the first time, we showed that the 3'-5'-hydroxylated congener [(E)-HST-1] of trans-resveratrol, synthesized in multigram scale, exerted potential chemotherapeutic property but was nonulcerogenic in nature, rather moderately accelerated healing of indomethacin-induced gastric ulceration. HST-1 did not suppress COX-1, COX-2 expression, and PGE(2) synthesis but reduced the level of inflammatory myeloperoxidase (MPO) activity. The healing was augmented primarily through the nitric oxide synthase (NOS)-dependent pathway. HST-1 treatment induced endothelial NOS (eNOS) expression and reduced inducible NOS (iNOS), resulting in increased eNOS/iNOS ratio. The selective iNOS inhibitor [L-N(6)-(1-iminoethyl) lysine hydrochloride] and nonselective NOS inhibitor (N(omega)-nitro-L-arginine methyl ester) treatment revealed that eNOS could be the probable molecular switch to accelerate the indomethacin-induced ulcer healing in HST-1-treated mice. Furthermore, the anticancer effect of HST-1 on U937 and K562 leukemia cell lines was found to be significantly better than that of trans-resveratrol. Overall, these established HST-1 as a potentially better anticancer compound than trans-resveratrol, considering it is devoid of any ulcerogenic side effects. In conclusion, for the first time, we showed that a novel analog of trans-resveratrol, HST-1, was devoid of ulcerogenic adversative effects of trans-resveratrol but retained potentially better anticancer property.
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PMID:Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice. 1906 40

Drug resistance continues to be a serious problem in cancer therapy. We investigated whether indomethacin, which inhibits cyclooxygenases, is able to overcome doxorubicin resistance in K562/ADR leukemia cells. Indomethacin at 10 microM increased the cytotoxicity of doxorubicin and vincristine in K562/ADR cells. Intracellular glutathione content was elevated in K562/ADR cells. Indomethacin treatment decreased glutathione content and glutathione-conjugates in K562/ADR cells. Increased expression of gamma-glutamylcysteine synthetase (gamma-GCS) was observed in K562/ADR cells, but this expression was decreased by indomethacin treatment. The activity of the gamma-GCS promoter from K562/ADR cells decreased after indomethacin treatment in MDA231 cells. These data strongly suggest that the cyclooxygenase inhibitor indomethacin increases the cytotoxicity of doxorubicin by decreasing the intracellular contents of glutathione and its conjugates with decreasing expression of gamma-GCS by inhibiting gamma-GCS promoter activity.
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PMID:Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of gamma-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells. 1915 36


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