Contribution of Gene-Specific Lesions, DNA-Replication-Associated Damage, and Subsequent Transcriptional Inhibition in Topoisomerase Inhibitor-Mediated Apoptosis in Lymphoma Cells

Muscarella, Donna E.; Rachlinski, Melissa K.; Sotiriadis, John; Bloom, Stephen E.

doi:10.1006/excr.1997.3832

Cited by 29 publications

(16 citation statements)

References 39 publications

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“…Actinomycin D, a relatively selective inhibitor of rRNA synthesis, inhibits Pol I transcription during the elongation step (35) and induces apoptosis in cancer cell lines (36). Inhibition of Pol I transcription at the elongation step leads to the formation of truncated pre-rRNA, which can be interpreted by the cell as breaks in rDNA.…”

Section: Discussionmentioning

confidence: 99%

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

et al. 2011

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Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell-and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

et al. 2011

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“…Interestingly, actinomycin D is an inducer of apoptosis, a genetically determined cell suicide program, in animals (Devitt et al, 1999;Li et al, 1999). Transcriptional suppression is a major event for apoptosis induction by actinomycin D (Muscarella et al, 1998). In addition, heat shock induces cell death in yeast (Davidson et al, 1996).…”

mentioning

confidence: 99%

“…It is thus not surprising that actinomycin D and heat shock treatments were able to induce an HR, which is a form of programmed cell death in plants (Dangl et al, 1996;Mittler and Lam, 1996), in leaves systemically infected with TMV. Because the response to actinomycin D (Muscarella et al, 1998) or heat shock (Lindquist, 1986) varies between cell lines or cell types, TMV-infected cells are probably more sensitive to actinomycin D or heat shock treatment than are uninfected cells. If TMV-infected NN tobacco leaves are treated with actinomycin D or subjected to heat shock, then transcription of specific housekeeping genes, including the DS9 gene, would be suppressed to a greater extent in infected cells than in uninfected cells.…”

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confidence: 99%

Reduced Levels of Chloroplast FtsH Protein in Tobacco Mosaic Virus–Infected Tobacco Leaves Accelerate the Hypersensitive Reaction

et al. 2000

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In tobacco cultivars resistant to tobacco mosaic virus (TMV), infection results in the death of the infected cells accompanying the formation of necrotic lesions. To identify the genes involved in this hypersensitive reaction, we isolated the cDNA of tobacco DS9, the transcript of which decreases before the appearance of necrotic lesions. The DS9 gene encodes a chloroplastic homolog of bacterial FtsH protein, which serves to maintain quality control of some cytoplasmic and membrane proteins. A large quantity of DS9 protein was found in healthy leaves, whereas the quantity of DS9 protein in infected leaves decreased before the lesions appeared. In transgenic tobacco plants containing less and more DS9 protein than wild-type plants, the necrotic lesions induced by TMV were smaller and larger, respectively, than those on wild-type plants. These results suggest that a decrease in the level of DS9 protein in TMV-infected cells, resulting in a subsequent loss of function of the chloroplasts, accelerates the hypersensitive reaction. INTRODUCTIONThe hypersensitive reaction (HR) is a plant defense system against pathogen attack. HR is defined as the rapid death of infected cells accompanying formation of necrotic lesions in which pathogens are thought to be enclosed (Goodman and Novacky, 1994). The HR of tobacco to tobacco mosaic virus (TMV) occurs in cultivars carrying the resistance gene N ( NN tobacco) but not in cultivars lacking the N gene ( nn tobacco) (Holmes, 1938; Whitham et al., 1994). Induction of the N gene-mediated HR requires the temperature to be below 22 to 26 Њ C (Kassanis, 1952;Shimomura, 1971; Weststeijn, 1981), suggesting that the gene can function at temperatures below this range.We previously observed that when TMV-inoculated leaves were treated with heat shock or actinomycin D, necrotic lesions were induced in not only NN but also in nn tobacco, even at 30 Њ C, a nonpermissive temperature for the N gene (Shimomura and Ohashi, 1971;Ohashi and Shimomura, 1972). In the actinomycin D-treated leaves in which necrotic lesions were induced, the synthesis of nucleic acid in the host plant was greatly suppressed, whereas the synthesis of TMV RNA was suppressed only slightly (Shimomura and Ohashi, 1980). In contrast to treatment with actinomycin D, treatment with other chemicals, including rifampicin, 2-thiouracil, and cycloheximide, which suppress RNA or protein synthesis in both the TMV and the host plant, did not induce necrotic lesions to form (Ohashi and Shimomura, 1972). Given that actinomycin D forms intercalation complexes with DNA, thereby blocking transcription (Waring, 1981), and that heat shock suppresses transcription of housekeeping genes (Lindquist, 1986;Nover et al., 1989), we hypothesized that suppressing the transcription of certain housekeeping genes in NN tobacco plants after infection with TMV could induce the HR.To isolate such candidate genes, we used a synchronous HR-inducing system based on a temperature shift. Incubation at 30 Њ C of TMV-infected NN tobacco leaves results in 1 Curr...

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“…Feature of lymphocyte/neutrophil apoptosis induced by cytotoxic compounds observed in the in vitro assay and the in vivo experiments As described above, there were species differences for each compound, and although the mechanisms for the first signal for induction of apoptosis by drugs are often not known, it is anticipated that there is a variety of initial mechanisms by which anticancer compounds induce apoptosis (Clarke et al, 1997;Muscarella et al, 1998;Goering et al, 1999;Fulda et al, 2001;Milner et al, 2002), including the involvement of p53, Bcl-2 family, caspases and Fas/FasL pathway (Biswas et al, 2001;Lorenzo et al, 2002) and relating to the drug-resistance to apoptosis (Weller, 1998;Makin and Hickman, 2000). Concerning lymphocyte apoptosis, dog lymphocytes were most susceptible to apoptosis; on the other hand, human lymphocytes were relatively resistant.…”

Section: Figmentioning

confidence: 99%

“…Recently, the apoptosis of lymphocytes has been elucidated as another mechanism involved in leukopenia induction from the following facts. Antitumor agents including actinomycin D, doxorubicin, etoposide, and camptothecin induce not only apoptosis of tumor cells (Kaufman, 1989;Bertrand et al, 1991;Muscarella et al, 1998) but that of lymphocytes (Walker et al, 1991;Zaleskis et al, 1994;Potter et al, 1999). Apoptosis of leukocytes is also caused by many other class of cytotoxic compounds, which include cycloheximide (Payne et al, 1994;Lemaire et al, 1999), dexamethazone (Krishna et al, 1995) and methylprednisolone (Migita et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

In vitro cytotoxicity assay to screen compounds for apoptosis-inducing potential on lymphocytes and neutrophils.

Nagami¹,

Kawashima²,

Kuno³

et al. 2002

J. Toxicol. Sci.

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-In vitro cytotoxicity assay to screen compounds for apoptosis-inducing potential on lymphocytes and neutrophils was investigated. Mouse, rat, dog, and human whole blood were incubated for 4 and 6 hr with actinomycin D, camptothecin, cortisone acetate, cycloheximide, doxorubicin, etoposide, 5-FU, mitomycin C and puromycin. Apoptotic lymphocytes and neutrophils were counted. All test compounds induced in vitro apoptosis of lymphocytes and/or neutrophils, but there were different potencies among the test compounds and there were also species differences in susceptibility. To investigate the in vivo effects of etoposide and cycloheximide which induced apoptosis of rat lymphocytes and that of rat lymphocytes and neutrophils, respectively, in in vitro assay, rats were intravenously administered either etoposide at 12.5, 25 or 50 mg/kg or cycloheximide at 1.25, 2.5 or 5 mg/kg. Etoposide caused decreases of circulating lymphocytes at 3 hr after administration in a dose-dependent manner, -16, -25 and -51%. Although cycloheximide caused neither decreased lymphocyte nor neutrophil counts, apoptosis in 30% of neutrophils was observed in rats receiving 5 mg/kg at 3 hr after administration. Etoposide at 50 mg/kg and cycloheximide at 5 mg/kg caused lymphocyte apoptosis in the spleen, thymus, mesenteric lymph nodes, bone marrow, and Peyer's patch from 1 to 6 hr after administration, with the maximum changes at 3 hr. In addition to apoptosis of these organs, cycloheximide at 5 mg/kg caused apoptosis of polymorphonuclear cells in the lamina propria of the small intestine. Therefore, it was found that the changes seen in the in vivo experiments considerably reflected the changes seen in the in vitro experiments.From these results, apoptosis is probably one of the major mechanisms for leukocyte toxicity induced by cytotoxic compounds, and the in vitro assay to screen compounds for acute apoptosis-inducing potential on lymphocytes and neutrophils would be useful as a primary screening method for animal toxicity studies. It may also be useful for risk assessments in advance of clinical trials.

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Contribution of Gene-Specific Lesions, DNA-Replication-Associated Damage, and Subsequent Transcriptional Inhibition in Topoisomerase Inhibitor-Mediated Apoptosis in Lymphoma Cells

Cited by 29 publications

References 39 publications

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

Reduced Levels of Chloroplast FtsH Protein in Tobacco Mosaic Virus–Infected Tobacco Leaves Accelerate the Hypersensitive Reaction

In vitro cytotoxicity assay to screen compounds for apoptosis-inducing potential on lymphocytes and neutrophils.

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