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PubMed1999

1',2',3',4'-tetradehydrotubulosine, a cytotoxic alkaloid from Pogonopus speciosus.

Bioassay-guided phytochemical investigation of the stems of Pogonopus speciosus, using human oral epidermoid carcinoma (KB) cells as a monitor, led to the isolation of a novel alkaloid, 1',2', 3',4'-tetradehydrotubulosine (1), along with tubulosine (2) and psychotrine (3) as bioactive constituents. The structure of the novel compound was elucidated through 1D- and 2D-NMR spectroscopic methods. Alkaloids 1 and 3 showed weak cytotoxic activity against a panel of human cancer cell lines, with the potency of these compounds being markedly less than that of tubulosine (2).

Alkaloids↗

PubMedDate not supplied

Identification and evaluation of potential anti-cancer drugs on human neuroendocrine tumor cell lines.

UNLABELLED: The aim of this study was to investigate drug sensitivity in neuroendocrine tumor cell lines. MATERIALS AND METHODS: In vitro drug sensitivity screening was performed using the fluorometric microculture cytotoxicity assay in one human pancreatic carcinoid and two human bronchial carcinoid cell lines. In addition, a normal human retinal pigment epithelial cell line was used for comparison. A total of 18 drugs with different mechanisms of action were tested. RESULTS: The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC5o values <1 microM in all four cell lines. In addition, the three tumor cell lines showed sensitivity for sanguinarine, Bayll-7085, mitoxantrone, doxorubicin, beta-lapachone, NSC 95397 and CGP-74514A. CONCLUSION: The cell lines were sensitive for several drugs acting in different ways, covering a broad spectrum of mechanisms of action. Some of these compounds may possibly be used in clinical trials and show therapeutic effect in patients with neuroendocrine tumors.

Antineoplastic Agents↗

PubMed1984

Therapy of fluke infections in the past. A review.

Chemotherapy of trematode infections has been studied intensively in the past. The compounds so far used for the treatment of those parasitic infections were not satisfactory, however, because of their poor tolerability and/or their limited anthelmintic efficacy. Since the introduction of tartar emetic in 1918, a number of antimonial as well as non-antimonial preparations have been used for the treatment of schistosomiasis. In the treatment of clonorchiasis with antimony preparations, gentian violet, emetine HCl, chloroquine diphosphate and dithiazanine iodide, only temporary clinical improvement and negative or reduced egg counts could be achieved, but complete cure was not obtained. Although Hetol (or hexachloroparaxylol), prolonged administration of oral dehydroemetine and only two doses of niclofolan showed therapeutic effect on Clonorchis infection, side effects were observed in most of the treated cases. On the other hand, bithionol proved to be a drug of choice for paragonimiasis. However, the need of multiple doses and the many adverse reactions hampered its use in the field. Recently the newly developed praziquantel (2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1-a]+ ++isoquinolin -4-one, EMBAY 8440, Biltricide) proved to be safe and effective against trematodes and appears to be the drug of choice for infections due to all species of Schistosoma, Clonorchis sinensis, Opisthorchis viverrini, Paragonimus spp. and Metagonimus yokogawai in man.

Anthelmintics↗

PubMed1985

Cross-resistance of vinblastine- and taxol-resistant mutants of Chinese hamster ovary cells to other anticancer drugs.

Stable mutants resistant to the anticancer drug vinblastine (VinR mutants) have been isolated after a single selection step from Chinese hamster ovary cells. Of the two types of VinR mutants which are obtained, one class exhibits specific cross-resistance to only some of the microtubule inhibitors. However, the second type of mutants, which is affected in membrane permeability, exhibits cross-resistance to a wide variety of unrelated compounds. Both classes of VinR mutants showed codominant expression in cell hybrids formed between resistant and sensitive cells. The cross-resistance patterns of the VinR mutants and a single-step mutant resistant to the anticancer drug taxol (TaxR mutant) toward various anticancer drugs have been determined. The mutants resistant to both of these drugs showed significantly increased resistance toward aclarubicin, dactinomycin, doxorubicin, bisantrene, bruceantin, chromomycin A3, demecolcine, colchicine, daunorubicin, ellipticine, emetine, ethidium bromide, maytansine, mithramycin, mitoxantrone, nitidine chloride, olivomycin, podophyllotoxin, puromycin, taxol, vinblastine, vincristine, vindesine, teniposide, and etoposide. Interestingly, either one or both of the above mutants exhibited somewhat enhanced sensitivity toward vidarabine, acivicin, bleomycin, cisplatin, cytarabine, alpha-difluoromethyl-ornithine, 5-FU, tegafur, and tiazofurin. For a number of other anticancer drugs which were examined (chlorambucil, mitolactol, IMPY, hexamethylmelamine, hydroxyurea, diglycoaldehyde, methotrexate, mitoguazone, mitomycin, nocodazole, and 6-thioguanine), the level of resistance of these mutants was found to be unaltered. The information regarding cross-resistance and collateral sensitivity patterns of VinR and TaxR mutants should prove to be very useful in the design of drug combinations which could prove more effective in cancer chemotherapy.

Alkaloids↗

PubMed1995

Stimulatory and inhibitory effects of iron on photodynamic inactivation of leukemia cells.

The influence of exogenous iron on merocyanine 540 (MC540)-sensitized photoinactivation of leukemia cells has been investigated. Irradiation of murine L1210 or human HL-60 cells (approximately 10(6)/mL in 1% serum/RPMI medium) with broadband visible light in the presence of MC540 (2 microM) resulted in a progressive loss of clonally assessed cell viability. When added to cells 30 min before irradiation, the low polarity chelate, ferric 8-hydroxyquinoline [Fe(HQ)2, 0.5 microM] stimulated dye-sensitized photokilling, whereas high polarity chelates such as ferric 8-hydroxyquinoline-5-sulfonate [Fe(HQS)2, 0.5 microM] or ferric ethylenediaminetetraacetate (Fe.EDTA, 0.5 microM) had no no effect. A striking reversal of Fe(HQ)2-enhanced photokilling was observed upon increasing the preirradiation incubation time with Fe(HQ)2 such that a marked resistance (relative to non-iron-treated controls) was evident after 24 h. Cells exposed for 24 h to Fe(HQS)2 or Fe.EDTA showed similar or even greater resistance to photokilling. Like phototoxicity, H2O2-induced cytotoxicity was enhanced after a 30 min exposure of cells to Fe(HQ)2 but strongly repressed after 24 h. Immunoblot (western) analysis, using a polyclonal antibody to ferritin, revealed that cells exposed to Fe(HQ)2 for 24 h contained at least 12 times as much ferritin heavy chain as non-Fe(HQ)2-treated controls. Preincubating cells with emetine, an inhibitor of protein synthesis, prevented both ferritin induction and the development of hyperresistance. These findings, along with the observation that exogenous apoferritin protected L1210 cells against photokilling, suggest a possible role for ferritin in iron-stimulated photoresistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1997

Evidence of two mechanisms for the activation of the glucose transporter GLUT1 by anisomycin: p38(MAP kinase) activation and protein synthesis inhibition in mammalian cells.

1. Inhibitors of protein synthesis stimulate sugar transport in mammalian cells through activation of plasma membrane GLUT1, the housekeeping isoform of the glucose transporter. However, it has been reported that some of these compounds, in addition to their effect on protein synthesis, also activate protein kinases. 2. In the present study we have explored the role of these two effects on GLUT1 activation. In 3T3-L1 adipocytes and Clone 9 cells, stimulation of sugar transport by puromycin, a translational inhibitor that does not activate kinases, was not detectable until 90 min after exposure. In contrast, stimulation by anisomycin, a potent Jun-NH2-terminal kinase (JNK) agonist, exhibited no lag phase. An intermediate response was observed to emetine and cycloheximide, weak activators of JNK. 3. The potency of anisomycin to stimulate transport acutely (30 min of exposure) was 5- to 10-fold greater than for its chronic stimulation of transport, measured after 4 h of exposure. The stimulation of transport by a low concentration of anisomycin (0.3 microM) was transient, peaked at 30-60 min and it was inhibited (IC50 < 1 microM) by SB203580, which indicates that its mediator is not JNK, but the homologous p38(MAP kinase) (p38(MAPK)). In contrast, the responses to 4 h exposure to 300 microM anisomycin or puromycin were refractory to SB203580. 4. Exposure to anisomycin resulted in rapid activation of p38(MAPK). Activation of both p38(MAPK) and GLUT1 by 0.3 microM anisomycin was cancelled by puromycin. 5. We conclude that the activation of GLUT1 in response to anisomycin includes two components: a delayed component involving translational inhibition and a fast, puromycin-inhibitable component that is secondary to activation of p38(MAPK).

Adipose Tissue↗

PubMed2001

Sensitive determination of metal ions by liquid chromatography with tris(2,2'-bipyridine) ruthenium (II) complex electrogenerated chemiluminescence detection.

Emetine dithiocarbamate metal complex, which is prepared from emetine, carbon disulfide, and metal (II), was found to indicate a large chemiluminescence intensity on the electrogenerated chemiluminescence of tris(2,2'-bipyridine)ruthenium(II). Liquid chromatography equipped with the chemiluminescence detection was developed for analyzing trace metal ions by use of the metal complex formation. The mixture of the Cu(II) and Co(II) complexes as a model sample was injected into the LC system. The two metal complexes and an excess emetine were successfully separated. The Cu(II) and Co(II) complexes were determined over the range 1-300 nM (the detection limit of 650 fg) and 30-5000 nM (the detection limit of 17 pg), respectively.

2,2'-Dipyridyl↗

PubMed1995

New mechanisms of drug resistance in parasitic protozoa.

The main line of defense now available against parasitic protozoa--which are responsible for major diseases of humans and domestic animals--is chemotherapy. This defense is being eroded by drug resistance and, with few new drugs in the pipeline, prevention and circumvention of resistance are medical and veterinary priorities. Although studies of resistance mechanisms in parasites have lagged behind similar studies in bacteria and cancer cells, the tools to tackle this problem are rapidly improving. Transformation with exogenous DNA is now possible with all major parasitic protozoa of humans. Hence, putative resistance genes can be tested in sensitive protozoa, allowing an unambiguous reconstruction of resistance mechanisms. Gene cloning, the polymerase chain reaction, and monoclonal antibodies against resistance-related proteins have made it possible to analyze potential resistance mechanisms in the few parasites that can be obtained from infected people. Hence, the prospect of applying new knowledge about resistance mechanisms to parasites in patients is good, even though today virtually all knowledge pertains to parasites selected for resistance in the laboratory. Resistance mechanisms highlighted in this review include: 1. Decrease of drug uptake because of the loss of a transporter required for uptake. This decrease contributes to resistance to arsenicals and diamidines in African trypanosomes. 2. The export of drugs from the parasite by P-glycoproteins and other traffic ATPases. This export could potentially be an important mechanism of resistance, as these proteins are richly represented in the few protozoa analyzed. There are indications that such transmembrane transporters can be involved in resistance to emetine in Entamoeba spp., to mefloquine in Plasmodium spp., and to antimonials in Leishmania spp. 3. The possible involvement of the P-glycoprotein encoded by the Plasmodium falciparum pfmdr1 gene in chloroquine resistance. We present the available data that lead to the conclusion that overproduction of the wild-type version of this protein results in chloroquine hypersensitivity rather than resistance. 4. The involvement of the PgpA P-glycoprotein of Leishmania spp. in low-level resistance to arsenite and antimonials. We raise the possibility that this protein transports glutathione conjugates of arsenite and antimonials rather than the compounds themselves. 5. Loss of drug activation as the main mechanism of metronidazole resistance in Trichomonas and Giardia spp. Recent evidence indicates that a decrease of the proximal cellular electron donor for metronidazole activation, ferredoxin, is the main cause of resistance in Trichomonas. 6. Resistance arising through alteration of drug targets. The amino acid substitutions in the dihydrofolate reductase-thymidylate synthase of Plasmodium spp. are good examples of this mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Targeting heat shock response to sensitize cancer cells to proteasome and Hsp90 inhibitors.

Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression of such induction may sensitize cancer cells to these drugs. Here, we knocked out the major heat shock transcription factor HSF-1 in several cancer cell lines using small interfering RNA and showed that such cells, which can no longer induce Hsps in response to proteasome and Hsp90 inhibitors, become more sensitive to these drugs. Furthermore, we developed a high-throughput screen for small molecules that inhibit induction of Hsps. The first step was a cell-based screen for inhibitors of Hsps-mediated luciferase refolding followed by a counterscreen for toxicity. The second step was a direct testing for inhibition of Hsp induction by immunoblotting with anti-Hsp72 antibody. After screening of 20,000 compounds from several diversity libraries, we focused on a compound we called NZ28, which potently inhibited induction of Hsps by heat shock, proteasome, and Hsp90 inhibitors in a variety of cell lines, and showed no significant toxicity. After testing of a set of analogues of NZ28, we identified a structural element that was critical for the activity. We also identified another inhibitor of the Hsp induction that was practically nontoxic. This compound, which we called emunin, strongly sensitized myeloma cells to proteasome and Hsp90 inhibitors and prostate carcinoma cells to proteasome inhibitors. This work indicates that targeting the heat shock response may facilitate use of proteasome and Hsp90 inhibitors for cancer treatment.

Animals↗

PubMed1975

Inhibition of protein synthesis in intact HeLa cells.

Polysome analysis has proved to be a sensitive probe for the mode of action of inhibitors of protein synthesis in intact HeLa cells. To classify the active compounds as inhibitors of initiation, elongation, or termination, their effects on the cellular polyribosome pattern were compared under three conditions. These conditions tested (i) their direct effect on the polyribosome profile; (ii) their effect on ribosome run-off produced by hypertonicity; and (iii) their effects on recovery from hypertonicity. Using this technique, diacetoxyscirpenol, 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamide, and three alkaloids, harringtonine, isoharringtonine, and homoharringtonine, were found to be inhibitors of initiation. Polysome analysis indicated that in HeLa cells 7.8 x 10(-7) M pactamycin, which inhibited protein synthesis 94%, interfered with elongation as well as initiation under these conditions. Emetine, anisomycin, cycloheximide, and trichodermin each gave polysome patterns consistent with inhibition of elongation. Fusidic acid and aurintricarboxylic acid inhibited incorporation of [(14)C]leucine into intact HeLa cells, but polysome analysis did not localize any specific inhibitory effects to the initiation, elongation, or termination steps of protein synthesis. The use of specific inhibitors of initiation of protein synthesis has indicated that most, if not all, mammalian messenger ribonucleic acids contain a single initiation site.

Amino Acids↗

PubMed1993

Release from the metaphase I block in invertebrate oocytes: possible involvement of Ca2+/calmodulin-dependent kinase III.

Full grown mature oocytes of the prosobranch gastropod mollusc Patella or the bivalves Mytilus or Ruditapes provide an excellent model for studying the mechanisms which trigger cyclin degradation and exit from the M phase. They are naturally arrested in metaphase of the first maturation division and their fertilization or artificial activation rapidly results in destruction of the cyclins and completion of meiosis. In this paper, we establish the presence of Ca2+/calmodulin-dependent kinase III or eEF-2 kinase in these oocytes and describe how the protein synthesis inhibitor emetine is able to release them from the metaphase block. Using the fluorescent Ca2+ indicator dye, fluo-3, we demonstrate moreover that both fertilization or KCl-dependent activation of Ruditapes and Mytilus oocytes actually trigger a measurable transient increase in cytosolic free Ca2+ concentration. We also show that the activations triggered by these signals as well as by the ionophore A 23187 can be reversibly blocked by the calmodulin antagonists TFP (30 microM) and W7 (100 microM), while these drugs have no effect upon emetine-dependent activations. Finally, we report that the rate of protein synthesis, measured in pulse experiments, decreases at each meiotic and mitotic cleavage following fertilization of metaphase I-arrested oocytes of Mytilus. On the basis of these experiments and as a working hypothesis, we thus propose that the Ca2+ surge which activates the oocyte may inhibit protein synthesis by triggering a transient phosphorylation of eEF-2. This would result in disappearance of the putative short-lived proteins which protect cyclins from degradation during the metaphase block.

Anaphase↗

PubMed1989

Isolation and characterization of dominant, pleiotropic drug-resistance mutants in Chlamydomonas reinhardtii.

Three independent pleiotropic drug-resistance (pdr) mutants were isolated by selecting for resistance to the anti-microtubule herbicides amiprophos-methyl (APM) and oryzalin (ORY). These three mutants and a previously isolated mutant, ani1 (anisomycin resistance), were semi-dominant in heterozygous diploids, and they displayed varying degrees of resistance to structurally and functionally unrelated inhibitors such as cycloheximide, cryptopleurine, emetine, atrazine, and nonidet P-40. Linkage analysis and genetic mapping suggested that three of the four mutants, including ani1, define a single locus, here named pdr1. The fourth mutant defined a new locus, pdr2, which is located on the left arm of linkage group VI. One pdr1 mutant exhibited unusual genetic interactions, including enhanced ts-lethality and synergistic increases in drug resistance, when combined with pdr2-1 and with herbicide-resistant alleles of three other genes.

Anisomycin↗

PubMed1995

The phosphodiesterase inhibitor SQ 20006 selectively blocks mitogen activation of p70S6k and transition to S phase of the cell division cycle without affecting the steady state phosphorylation of eIF-4E.

In quiescent cells high levels of protein synthesis are required in order to re-enter the cell cycle upon stimulation. Initiation of polypeptide synthesis is the step most often subject to regulation, controlled in part by phosphorylation of 40 S ribosomal protein S6 and a number of initiation factors. The kinase responsible for S6 phosphorylation is p70S6k. We now show that the p70S6k pathway can be selectively blocked by the aminopurine analogue, SQ 20006. This agent is known to raise cAMP levels, resulting in activation of protein kinase A. We present evidence that the increase in cAMP is not responsible for the inhibitory effect observed. We also show that SQ 20006 can prevent the activation of p70S6k in a rapid and reversible manner. The compound does not exert its inhibitory activity on p70S6k but can inhibit in vitro two protein kinase C isozymes (alpha and gamma). In a B lymphoblastoid cell line, treatment with SQ 20006 results in inhibition of protein synthesis at the initiation stage. In contrast, when tested directly upon the translational machinery in the reticulocyte lysate, inhibition is manifest at both the level of initiation and elongation. The role of protein kinase A in the modulation of p70S6k and the rate of translation is discussed.

1-Methyl-3-isobutylxanthine↗

PubMed1995

Long-term exposure to chromium(VI) oxide leads to defects in sulfate transport system in Chinese hamster ovary cells.

Chromium(VI) resistant Chinese hamster ovary (CHO) cell lines were established in this study by exposing parental CHO-K1 cells to sequential increases in CrO3 concentration. The final concentration of CrO3 used for selection was 7 microM for Cr7 and 16 microM for Cr16 cells. Cr16-1 was a subclone derived from Cr16 cells. Next, these resistant cells were cultured in media without CrO3 for more than 6 months. The resistance of these cells to CrO3 was determined by colony-forming ability following a 24-h treatment. The LD50 of CrO3 for chromium(VI) resistant cells was at least 25-fold higher than that of the parental cells. The cellular growth rate, chromosome number, and the hprt mutation frequency of these chromium(VI) resistant cells were quite similar to their parental cells. The glutathione level, glutathione S-transferase, catalase activity, and metallothionine mRNA level in Cr7 and Cr16-1 cells were not significantly different from their parental cells. Furthermore, Cr16-1 cells were as sensitive as CHO-K1 cells to free-radical generating agents, including hydrogen peroxide, nickel chloride, and methanesulfonate methyl ester, and emetine, i.e., a protein synthesis inhibitor. The uptake of chromium(VI) and the remaining amount of this metal in these resistant and the parental cell lines were assayed by atomic absorption spectrophotometry. Experimental results indicated that a vastly smaller amount of CrO3 entered the resistant cell lines than their parental cells did. A comparison was made of the sulfate uptake abilities of CHO-K1 and chromium(VI) resistant cell lines. These results revealed that the uptake of sulfate anion was substantially reduced in Cr7 and Cr16-1 cells. Extracellular chloride reduced sulfate uptake in CHO-K1 but not in Cr16-1 cells. Therefore, the major causative for chromium(VI) resistance in these resistant cells could possibly be due to the defects in SO4(2-)/C1- transport system for uptake chromium(VI).

Animals↗

PubMed1979

Multihormonal control of tyrosine aminotransferase in isolated liver cells.

The regulation of tyrosine aminotransferase activity by glucocorticoids and cyclic AMP was investigated in isolated liver parenchymal cell suspensions. The induction and maintenance of elevated levels of tyrosine aminotransferase activity in liver cells were completely dependent upon the presence of both the synthetic glucocorticoid, dexamethasone, and glucagon of dibutyryl cyclic AMP. No induction was observed when any of these compounds were tested alone. Immunotitration experiments revealed that the 6- to 7-fold increase in tyrosine aminotransferase activity following the addition of dexamethasone and glucagon was accompanied by a parallel increase in the amount of immunologically reactive enzyme protein. Pulse-labeling experiments established that this increase in enzyme protein could be fully accounted for by a corresponding increase in rate of synthesis of tyrosine aminotransferase. Neither hormone had any effect on the rate of degradation of the enzyme. The increase in tyrosine aminotransferase synthesis evoked by the presence of both hormones was blocked by the addition of actinomycin D or cycloheximide to the medium, demonstrating that RNA and protein synthesis were required for the induction of enzyme activity. By varying the time and order of addition of the inducers and inhibitions, evidence was obtained that the hormones act sequentially. The steroid hormone acts first, presumably to increase the level of functional tyrosine aminotransferase mRNA or its precursor. The processing of this precursor to a translatable form or the specific translation of tyrosine aminotransferase mRNA is apparently dependent upon a specific cyclic AMP-controlled process. In vivo experiments demonstrated that both glucocorticoids and cyclic AMP increase the level of functional tyrosine aminotransferase mRNA in the liver. The actions of the steroid hormone and cyclic nucleotide were blocked by alpha amanitin, establishing the requirement for ongoing gene transcription. The protein synthesis inhibitors, cycloheximide, emetine, and puromycin, were as effective as cyclic AMP in increasing tyrosine aminotransferase mRNA activity. The action of these inhibitors is probably related to their ability to elevate hepatic intracellular cyclic AMP levels, thus mimicking cyclic AMP administration. Extension of these in vivo studies to isolated liver cells will provide a valuable system for investigating the regulation of gene expression by glucocorticoids and cyclic AMP.

Animals↗