Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycolysis is known to be the primary energy source in cancer cells. We investigated here the effect of local anesthetics, lidocaine and bupivacaine, on the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis, and on ATP levels and cell viability in B16 melanoma cells. We found that both drugs induced a significant, dose-dependent reduction in the levels of glucose 1,6-bisphosphate, fructose 1, 6-bisphosphate, ATP, and cell viability. Bupivacaine was more potent than lidocaine. The decrease in glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, induced by the local anesthetics, preceded the reduction in the viability of melanoma cells, indicating that these are early changes and not a result of cell death. Cell viability was reduced in a close correlation with the fall in ATP. These findings suggest that the fall in the levels of the two signal allosteric regulators of glycolysis, induced by the local anesthetics, is one of the mechanisms that causes a reduction in glycolysis and ATP levels, which eventually leads to melanoma cell death. These experiments suggest that local anesthetics, and especially bupivacaine, are most promising agents in the treatment of melanoma.
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PMID:Local anesthetics induce a decrease in the levels of glucose 1, 6-bisphosphate, fructose 1,6-bisphosphate, and ATP, and in the viability of melanoma cells. 1065 56

Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. An important mechanism that controls glycolysis is the reversible binding of glycolytic enzymes to cytoskeleton. We report here that the local anesthetics, lidocaine and bupivacaine, induced a dose-dependent detachment of the glycolytic enzymes, phosphofructokinase (EC 2.7.1.11) and aldolase (EC 4.1.2.13), from cytoskeleton of B16 melanoma cells. The detachment of glycolytic enzymes from cytoskeleton would reduce the provision of local ATP, in the vicinity of cytoskeleton-membrane and would also affect cytoskeleton structure. We show here that the local anesthetics decreased the viability of melanoma cells. The detachment of the glycolytic enzymes from cytoskeleton, induced by the drugs, preceded melanoma cell death, which indicates that this is an early effect and not a result of cell death. Bupivacaine was more potent than lidocaine both on the glycolytic enzymes and on cell viability. The present results suggest that local anesthetics, and especially bupivacaine, are promising drugs for the treatment of melanoma.
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PMID:Detachment of the glycolytic enzymes, phosphofructokinase and aldolase, from cytoskeleton of melanoma cells, induced by local anesthetics. 1072 Apr 43

Genes MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 code for antigens that are recognized on melanoma cells by autologous CTLs. Because the pattern of expression of these genes results in the presence of antigens on many tumors of various histological types and not on normal tissues, these antigens qualify for cancer immunotherapy. To identify new genes with tumor-specific expression, we applied a cDNA subtraction approach, ie., representational difference analysis, to a human sarcoma cell line. We obtained two cDNA clones that appeared to be tumor specific. The corresponding genes were named SAGE and HAGE because they have the same pattern of expression as genes of the MAGE family. SAGE encodes a putative protein of 904 amino acids and shows no homology to any recorded gene. Like the MAGE-A genes, it is located in the q28 region of chromosome X. Expression of gene SAGE was observed mainly in bladder carcinoma, lung carcinoma, and head and neck carcinoma but not in normal tissues, with the exception of testis. Gene HAGE, which is located on chromosome 6, encodes a putative protein of 648 amino acids. This protein is a new member of the DEAD-box family of ATP-dependent RNA helicases. Gene HAGE is expressed in many tumors of various histological types at a level that is 100-fold higher than the level observed in normal tissues except testis. Because of this tumor-specific expression, genes SAGE and HAGE ought to encode antigens that could be useful for antitumoral therapeutic vaccination.
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PMID:Identification on a human sarcoma of two new genes with tumor-specific expression. 1091 59

Vascular endothelial growth factor, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. Using rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors. Biochemical kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor beta kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP. Cocrystallographic studies of SU6668 in the catalytic domain of FGF receptor 1 substantiated the adenine mimetic properties of its oxindole core. Molecular modeling of SU6668 in the ATP binding pockets of the FIk-1/KDR and PDGF receptor kinases provided insight to explain the relative potency and selectivity of SU6668 for these receptors. In cellular systems, SU6668 inhibited receptor tyrosine phosphorylation and mitogenesis after stimulation of cells by appropriate ligands. Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin. Furthermore, intravital multifluorescence videomicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model revealed that SU6668 treatment suppressed tumor angiogenesis. Finally, SU6668 treatment induced striking regression of large established human tumor xenografts. Investigations of SU6668 activity in cancer patients are ongoing in Phase I clinical trials.
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PMID:SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. 1094 23

S16020-2, a new olivacine derivative and a topoisomerase II inhibitor, has recently entered clinical trials. New analogues and derivatives have been synthesized from the S16020-2 compound. Preliminary data indicate that S30972-1, one of these S16020-2 derivatives, may exhibit a comparatively higher level of antitumor potency associated with an improved therapeutic index than does S16020-2. The antitumor activities of S16020-2 and S30972-1 were therefore characterized both in vitro and in vivo, with Adriamycin and etoposide chosen as reference compounds. The in vitro data show that S30972-1 is a topoisomerase II inhibitor, mediating its activity through an ATP-dependent mechanism such as S16020-2. The two olivacine derivatives exhibited similar activities in vitro at the levels of the global growth of six human cancer cell lines, of the induction of apoptosis, and of the G2 cell cycle phase arrest. The in vivo antitumor activity characterization included the use of two murine leukemia types (P388-LEU and L1210-LEU), two murine lymphoma-like models (P388-LYM and L1210-LYM), two mammary adenocarcinomas (MXT-HI and MXT-HS), and one melanoma (B16). The data show that S30972-1 is actually more efficient in vivo than S16020-2, a feature that may relate to the fact that S30972-1 is less toxic than S16020-2. The S30972-1 compound exhibited in vivo a level of antitumor activity that was also actually higher than that exhibited by Adriamycin and similar to that exhibited by etoposide.
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PMID:In vitro and in vivo pharmacological characterizations of the antitumor properties of two new olivacine derivatives, S16020-2 and S30972-1. 1099 72

Topoisomerases I and II unravel DNA during transcription, DNA replication and DNA repair. Inhibitors of both enzymes are important anticancer drugs, but only now are combined inhibitors becoming available for clinical use. In this study we have used an ATP-based chemosensitivity assay to determine the activity of XR5000 and possible combinations against ovarian cancer, a tumor sensitive to current topoisomerase inhibitors, and melanoma, an insensitive tumor. A further six tumors of other types were also tested. The results from 20 ovarian cancer and 18 melanoma biopsies show remarkably little difference between the tumor types in terms of IC50, IC90 or two summary indices of chemosensitivity based on all of the concentrations tested. XR5000 on its own shows a steep concentration-response curve in most tumors, only achieving high reduction (above 95%) of ATP levels at 2440 ng/ml (6 microM). The results were often similar to the combination of etoposide and topotecan, particularly at the higher concentrations tested. The combinations with greatest activity in ovarian cancer were with paclitaxel or cisplatin, while melanoma showed greatest improvement with paclitaxel or treosulfan. The results are encouraging for the clinical introduction of this agent, and suggest that it will be effective in combination with currently available drugs for both ovarian cancer and melanoma.
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PMID:Ex vivo activity of XR5000 against solid tumors. 1100 88

Melanotransferrin (MTf) is a membrane-bound transferrin (Tf) homologue that is found at high levels in melanoma cells. MTf has many characteristics in common with serum Tf and previous studies have shown that it can bind Fe. This has led to speculation that MTf may be involved in Fe transport. Because Fe is required for a variety of metabolic reactions including ATP and DNA synthesis, MTf could play a role in proliferation. However, recently it has been shown that MTf plays very little role in Fe uptake by melanoma cells, and unlike other Fe transport molecules (e.g. the transferrin receptor), its expression is not controlled by Fe. In the present review the function of MTf is discussed in relation to data suggesting other roles apart from Fe uptake.
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PMID:The membrane-bound transferrin homologue melanotransferrin: roles other than iron transport? 1286 Apr 20

Adriamycin (ADR), one of the major antitumor agents used for the clinical treatment of a wide variety of human cancers and its glutathione(GSH)-conjugated adduct, ADRIGLU, induced apoptosis in K562 erythroleukemia and TVM-A12 clone 2 melanoma human cell lines. We have previously reported that ADR has nuclear localization and that ADRIGLU localizes exclusively in the cytoplasm. During ADR or ADRIGLU treatment, significant depletion of the cell energy state, demonstrated by a reduction in high-energy phosphates (ATP and GTP) and a decrease in energy charge potential (ECP), were recorded between 2 hours and 24 hours, by HPLC analysis. Transmission electron microscopy also revealed that between 2 hours and 24 hours of ADR or ADRIGLU treatment, mitochondria underwent evident morphological changes, from an initial "high amplitude swelling state" to a "shrinkage state" and finally, in early apoptotic cells, to an "abnormal shrinkage state", in which a marked accumulation of pycnotic mitochondria was also observed. Confocal microscopic analysis, using the potential-sensitive dye JC-1, showed that inhibition of cell energy metabolism was preceded by a rapid decrease in mitochondrial transmembrane potential (delta psi m). With the progression of exposure time, the early depolarization of the mitochondrial membrane was followed by a transient reversion to normal delta psi m until, in apoptotic cells, almost all mitochondrial subpopulations appeared to be hyperpolarized. Our results indicated that mitochondria are actively involved in anthracycline-induced programmed cell death, suggesting a novel mechanism that may be common to all forms of apoptosis.
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PMID:Modifications of mitochondria in human tumor cells during anthracycline-induced apoptosis. 1113 38

Adriamycin (ADM), an anthracycline anticancer agent, is selectively stored in the nuclei of a variety of proliferating cells, but the precise mechanism of specific nuclear transport of ADM is not well known. Recently, we demonstrated that ADM shows high binding affinity to the cytoplasmic proteasomes of L1210 mouse leukemia cells and that taken up ADM by the cells selectively binds to proteasomes. Nuclear targeting of proteasome in proliferating cells may be mediated by the nuclear localization signals that are found in several of the alpha-type subunits of the 20S proteasome. To confirm nuclear transport of the ADM-proteasome complex, we synthesized a photoactive ADM analogue, N-(p-azidohenzoyl)-ADM, and generated a photoaffinity-labeled proteasome complex. The 26S proteasome purified from the cytosol of L1210 cells had a high affinity to N-(p-azidobenzoyl)-ADM. SDS-PAGE analysis of the photoaffinity-labeled proteasome showed that low molecular weight bands (approximately 21-31 kDa) of 20S proteasome had the highest photoaffinity. The photoaffinity-labeled proteasome was distributed in the cytoplasm and nuclei of digitonin-permeabilized L1210 and B-16 mouse melanoma cells in the presence of the cytosolic fraction and ATP. The rate of nuclear translocation of the proteasome was low in the absence of ATP. These results suggest that the proteasome is a specific translocator of ADM from the cytoplasm to the nucleus and that 20S proteasome components are the dominant ADM-binding sites. The nuclear transport of ADM-proteasome complex is regulated by an ATP-dependent nuclear pore-mediated mechanism.
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PMID:Mechanism of specific nuclear transport of adriamycin: the mode of nuclear translocation of adriamycin-proteasome complex. 1128 16

Because many tumors are acidic and hypoxic relative to normal tissues, glycolysis and oxygen consumption were investigated in early-passage human melanoma cells adapted to growth at pH 6.7. In the absence of glucose, the basal rate of oxygen consumption in low pH-adapted cells was 75% of that in cells grown at pH 7.3. The rate of lactic acid production in low pH-adapted cells was increased 4-fold by exposure to 16.7 mM glucose compared with a 10-fold increase in cells grown at pH 7.3. Furthermore, in low pH-adapted cells the rate of oxygen consumption was stimulated by the addition of glucose in contrast to the inhibition of oxygen consumption by elevated glucose in cells grown at pH 7.3 (i.e., the Crabtree effect). Both low pH-adapted cells and cells grown at pH 7.3 exposed to glucose plus 0.35 mM meta-iodo-benzylguanidine (MIBG), an inhibitor of mitochondrial respiration, had oxygen consumption reduced by approximately 60% and lactic acid production increased by approximately 65% relative to glucose alone. Although adaptation to growth at low pH was associated with a loss of the Crabtree effect and a higher ratio of oxygen consumption to lactic acid production, the rate of glycolysis was the same in both growth conditions in the presence of 0.1 mM dinitrophenol, an uncoupler of ATP synthesis. This indicates that the glycolytic capacity of low pH-adapted cells remains unchanged. Therefore, tumor acute acidification and oxygenation can be achieved by exposure to hyperglycemia combined with MIBG to improve therapeutic response.
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PMID:Absence of Crabtree effect in human melanoma cells adapted to growth at low pH: reversal by respiratory inhibitors. 1145 17


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