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)

To study cross-resistance to Photofrin (PF) photosensitization, a Friend leukaemia cell line (ADM-RFLC) with a high level of multi-drug resistance (MDR) and the parental sensitive cell line (FLC) have been used. PF uptake measured by HPLC shows a similar intracellular drug accumulation in both cell lines. The ID50s for cell growth inhibition by PF are also similar after exposure in the dark in the two cell lines, while after illumination they are slightly lower in ADM-RFLC than in FLC cells. Moreover, verapamil, known to reverse the MDR phenotype induced by P-glycoprotein over-expression (the drug efflux mechanism), affects equally ADM-RFLC and FLC cells sensitivity to PF. In addition, photodynamic treatment with PF did not reverse the resistance to rhodamine 123 and aclarubicin, but partly reverses resistance of ADM-RFLC cells to antitubulin drugs such as vinblastine or vincristine. These latter results could have clinical application in the treatment of tumours expressing the MDR phenotype.
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PMID:Cytotoxic and photodynamic effects of Photofrin on sensitive and multi-drug-resistant Friend leukaemia cells. 136 67

N-2-(Diethylaminoethyl)-9-hydroxyellipticinium chloride (DHE) is a structural analogue of ellipticine that is currently a leading compound for clinical trials. We have investigated the mechanism of DNA damage by this compound in murine L1210 leukemia cells using the method of alkaline elution. Although DHE was about 100-fold more cytotoxic than ellipticine, this increased cytotoxicity was not accompanied by greater amounts of DNA strand breakage or protein-DNA cross-linking. The single strand breaks caused by both compounds were protein associated and could be accounted for by the presence of double strand breaks. DNA damage by the compounds therefore was consistent with topoisomerase II inhibition. Unlike DHE, 80% of the DNA damage elicited by ellipticine was repaired within 1 h after removal of drug. For DHE, 20-h incubations in drug-free media were required to obtain 70% repair of single strand DNA breaks. These data indicated that although both ellipticine and DHE may inhibit topoisomerase II, the type of DNA damage which resulted in topoisomerase II inhibition by DHE was much more persistent than the DNA damage elicited by ellipticine.
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PMID:DNA damage and cytotoxicity in L1210 cells by ellipticine and a structural analogue, N-2-(diethylaminoethyl)-9-hydroxyellipticinium chloride. 154 Sep 60

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.
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PMID:Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl. 367 74

Singlet oxygen (1O2) can be quenched by water, lipids, proteins, nucleic acids and other small molecules. Polyunsaturated fatty acids (PUFA) of cells principally quench 1O2 by chemical mechanisms, producing lipid hydroperoxides, while proteins physically and chemically quench 1O2. Because cell lines can have different PUFA and protein levels, we hypothesized that 1O2 toxicity will vary between cell lines. We used Photofrin as a source of 1O2. Exposure of nine different leukemia cell lines (CEM, HEL, HL-60, K-562, KG-1, L1210, Molt-4, THP-1 and U-937) to Photofrin and light results in changes in membrane permeability (trypan blue) that vary with cell line. The greater the lipid content of the cell line, the less susceptible they are to membrane damage. When the cell media was supplemented with docosahexaenoic acid (DHA, 22:6), the overall unsaturation of cellular lipids increased. Photofrin and light resulted in increased radical formation in these supplemented cells compared to controls; however, there was no difference in membrane permeability between DHA-supplemented and control cells. Lipid-derived radical formation (electron paramagnetic resonance spin trapping) was cell line dependent; but no correlation between lipid content of cells and radical formation was found. However, we found that the greater the protein content of cells the more they were protected against membrane damage induced by Photofrin photosensitization. This suggests that cellular proteins are a key target for 1O2-mediated toxicity. A remarkable observation is that cell size correlates inversely with ability of cells to cope with a given flux of 1O2.
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PMID:Singlet oxygen toxicity is cell line-dependent: a study of lipid peroxidation in nine leukemia cell lines. 1062 99

The goal of our study was to investigate the mechanism by which changes in extracellular pH influence lipid peroxidation processes. Ferrous iron can react with hydroperoxides, via a Fenton-type reaction, to initiate free radical chain processes. Iron is more soluble at lower pH values, therefore we hypothesized that decreasing the environmental pH would lead to increased iron-mediated lipid peroxidation. We used Photofrin, a photosensitizer that produces singlet oxygen, to introduce lipid hydroperoxides into leukemia cells (HL-60, K-562, and L1210). Singlet oxygen reacts with the PUFA of cells producing lipid hydroperoxides. Using EPR spin trapping with POBN, free radical formation from HL-60 cells was only detected when Photofrin, light, and ferrous iron were present. Free radical formation increased with increasing iron concentration; in the absence of extracellular iron, radical formation was below the limit of detection and lipid hydroperoxides accumulated in the membrane. In the presence of iron, lipid-derived radical formation in cells is pH dependent; the lower the extracellular pH (7.5-5.5), the higher the free radical flux; the lower the pH, the greater the membrane permeability induced in K-562 cells, as determined by trypan blue dye exclusion. These data demonstrate that lipid peroxidation processes, mediated by iron, are enhanced with decreasing extracellular pH. Thus, acidic pH not only releases iron from "safe" sites, but this iron will also be more damaging.
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PMID:Acidic pH amplifies iron-mediated lipid peroxidation in cells. 1088 46

Singlet oxygen (1O2) is believed to be the major cytotoxic agent involved in photodynamic therapy (PDT). Measurement of 1O2 near-infrared (NIR) luminescence at 1270 nm in biological environments is confounded by the strongly reduced 1O2 lifetime and probably has never been achieved. We present evidence that this is now possible, using a new NIR-sensitive photomultiplier tube. Time-resolved 1O2 luminescence measurements were made in various solutions of aluminum tetrasulphonated phthalocyanine (AlS4Pc) and Photofrin. Measurements were also performed on suspensions of leukemia cells incubated with AlS4Pc, and a true intracellular component of the 1O2 signal was clearly identified. Time-resolved analysis showed a strongly reduced 1O2 lifetime and an increased photosensitizer triplet-state lifetime in the intracellular component. In vivo measurements were performed on normal skin and liver of Wistar rats sensitized with 50 mg/kg AlS4Pc. In each case, a small but statistically significant spectral peak was observed at 1270 nm. The 1O2 lifetime based on photon count rate measurements at 1270 nm was 0.03-0.18 micros, consistent with published upper limits. We believe that these are the first direct observations of PDT-generated intracellular and in vivo 102. The detector technology provides a new tool for PDT research and possibly clinical use.
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PMID:Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo. 1200 28

We examined the apoptotic effects of photodynamic therapy (PDT) in leukemia cells (HL60) and lymphoma cells (Raji). Moreover, we also investigated the relationship of apoptosis induced by PDT to heat shock protein (HSP) expression. To induce 80% of cell death by PDT, HL60 cells required 6 microg/mL and Raji cells required 9 microg/mL of Photofrin. PDT induced apoptosis in 77.2% of HL60 and in 0.4% of Raji at lethal dose (LD80) conditions. The cell line in which apoptosis is predisposed may be more susceptible to PDT compared with the cell line in which necrosis is predisposed. Furthermore, HSP-70 was expressed constitutively in Raji cells but not in HL60 cells. Heat treatment of HL60 cells induced expression of HSP-70 and resulted in significant reduction of PDT-mediated apoptosis. From the results of this experiment, it is suggestive that HSP-70 contributes to inhibition of apoptosis mediated by PDT.
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PMID:Inhibitory effect of heat shock protein 70 on apoptosis induced by photodynamic therapy in vitro. 1498 37

Polyunsaturated fatty acids located in leukemia cell membranes are excellent targets for peroxidation. They can significantly enhance the effectiveness of Photofrin-mediated photodynamic therapy (PDT)-induced cell killing. In this study, the peroxidizability of conjugated fatty acid isomers (9c,11t-linoleic acid and 9c,11c-linoleic acid) and polyunsaturated fatty acids (PUFAs; linoleic acid, gamma-linolenic acid and arachidonic acid) with 2,2'-azo-bis(2-amidinpropane)dihydrochloride, soybean lipoxygenase and photomediated peroxidation are compared with each other. Peroxidation was determined using different methods: by means of gas chromatography to estimate the fatty acid (FA) consumption, by photometry for the level of FA peroxides or phospholipid peroxides and by definition of the content of malondialdehyde for thiobarbituric acid reactive substances (TBARS). The results suggest that the generation of oxidation products from individual FAs indicate a different formation rate of oxidation products. Radical FA peroxides were produced most by polyunsaturated arachidonic acid, followed by linoleic acid and gamma-linolenic acid, whereas conjugated FA isomers did not generate peroxides. Accordingly, the levels of lipid peroxides and TBARS were substantially increased after incorporation and oxidation of polyunsaturated FAs into U937 cells and could significantly enhance the effectiveness of Photofrin-PDT-induced cytotoxicity. The results showed that PUFA, but not conjugated FA supplementation of U937 cells, can act as a PDT amplification factor.
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PMID:Polyunsaturated but not conjugated linoleic acid supplementation of leukemic U937 cells can act as an amplification factor for photofrin-mediated photodynamic therapy. 1646 43

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a number of pathologic abnormalities, including adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The viral oncoprotein Tax has been implicated in the pathogenesis of these diseases. Recently, cell-free Tax was detected in the cerebrospinal fluid of HAM/TSP patients, implying that extracellular Tax may be relevant to neurologic disease. Additionally, the presence of a nuclear export signal within Tax and its active secretion has been demonstrated in vitro. However, the mechanism of Tax secretion remains to be established. Studies reported herein elucidate the process of Tax secretion and identify domains of Tax critical to its subcellular localization and secretion. Tax was shown to interact with a number of cellular secretory pathway proteins in both the model cell line BHK (baby hamster kidney)-21 and an HTLV-1-infected T cell line, C8166, physiologically relevant to HTLV-1-induced disease. Silencing of selected components of the secretory pathway affected Tax secretion, further confirming regulated secretion of Tax. Additionally, mutations in two putative secretory signals within Tax DHE and YTNI resulted in aberrant subcellular localization of Tax and significantly altered protein secretion. Together, these studies demonstrate that Tax secretion is a regulated event facilitated by its interactions with proteins of the cellular secretory pathway and the presence of secretory signals within the carboxyl-terminal domain of the protein.
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PMID:Identification of human T cell leukemia virus type 1 tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein. 1789 46

Macroautophagy/autophagy, a pathway by which cellular components are sequestered and degraded in response to homeostatic and cell stress-related signals, is required to preserve hematopoietic stem and progenitor cell function. Loss of chromosomal regions carrying autophagy genes and decreased autophagy gene expression are characteristic of acute myeloid leukemia (AML) cells. Deficiency of autophagy proteins is also linked to an altered AML metabolic profile; altered metabolism has recently emerged as a potential druggable target in AML. Here, we sought to understand the mitochondria-specific changes that occur in leukemia cells after knockdown of BNIP3L/Nix or SQSTM1/p62, which are two autophagy genes involved in mitochondrial clearance and are downregulated in primary AML cells. Mitochondrial function, as measured by changes in endogenous levels of reactive oxygen species (ROS) and mitochondrial membrane potential, was altered in leukemia cells deficient in these autophagy genes. Further, these AML cells were increasingly sensitive to mitochondria-targeting drugs while displaying little change in sensitivity to DNA-targeting agents. These findings suggest that BNIP3L or SQSTM1 may be useful prognostic markers to identify AML patients suitable for mitochondria-targeted therapies. Abbreviations: AML: acute myeloid leukemia; DHE: dihydroethidium; mtDNA: mitochondrial DNA; NAO: 10-N-nonyl acridine orange; PD: population doubling; R123: rhodamine 123; ROS: reactive oxygen species; TRC: transduced scramble controls.
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PMID:Knockdown of BNIP3L or SQSTM1 alters cellular response to mitochondria target drugs. 3056 11


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