Anthracycline Antibiotic Blockade of SV40 T Antigen Helicase Action

Bachur, Nicholas R.; Lun, Lapman; Sun, Pei Ming; Trubey, Charles M.; Elliott, E.Elizabeth; Egorin, Merrill J.; Malkas, Linda H.; Hickey, Robert J.

doi:10.1016/s0006-2952(97)00617-5

Cited by 19 publications

(13 citation statements)

References 31 publications

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“…The inhibition by nogalamycin depends on the source of the enzyme and is highly variable because the IC 50 value for this compound ranged from 0.1 to N650 μM for various viral helicases (Borowski et al, 2002). The anthracyclines are also universal inhibitors of most of the helicases tested so far, such as PcDDH45, HDHII, SV40 large T antigen and the viral helicases of the Flaviviridae family (Tuteja et al, 1997;Bachur et al, 1998;Pham and Tuteja, 2002;Tuteja et al, 2003). The compounds used in the present .…”

Section: Discussionmentioning

confidence: 99%

Characterization of replication fork and phosphorylation stimulated Plasmodium falciparum helicase 45

Pradhan

Hussain

Tuteja

2008

Gene

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Section: Discussionmentioning

confidence: 99%

Characterization of replication fork and phosphorylation stimulated Plasmodium falciparum helicase 45

Pradhan

Hussain

Tuteja

2008

Gene

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“…Inhibition of helicase activity has been reported for several DNA-binding agents, including many antitumor antibiotics such as anthracyclines (49 -56). In these cases, it is most likely that inhibition is caused by the formation of a strong complex between the DNA-binding ligand and the template DNA, which impede the action of the helicase (49). There is considerable evidence that inhibition of helicase activity by such compounds may play some role in their anticancer activity (57), but the effect of helicase inhibition in cancer cells has not been extensively studied.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DNA Replication and Induction of S Phase Cell Cycle Arrest by G-rich Oligonucleotides

Hamhouyia²,

Thomas³

et al. 2001

Journal of Biological Chemistry

154

161

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The discovery of G-rich oligonucleotides (GROs) that have non-antisense antiproliferative activity against a number of cancer cell lines has been recently described. This biological activity of GROs was found to be associated with their ability to form stable G-quartet-containing structures and their binding to a specific cellular protein, most likely nucleolin (Bates, P. J., Kahlon, J. B., Thomas, S. D., Trent, J. O., and Miller, D. M. (1999) J. Biol. Chem. 274, 26369 -26377). In this report, we further investigate the novel mechanism of GRO activity by examining their effects on cell cycle progression and on nucleic acid and protein biosynthesis. Cell cycle analysis of several tumor cell lines showed that cells accumulate in S phase in response to treatment with an active GRO. Analysis of 5-bromodeoxyuridine incorporation by these cells indicated the absence of de novo DNA synthesis, suggesting an arrest of the cell cycle predominantly in S phase. At the same time point, RNA and protein synthesis were found to be ongoing, indicating that arrest of DNA replication is a primary event in GRO-mediated inhibition of proliferation. This specific blockade of DNA replication eventually resulted in altered cell morphology and induction of apoptosis. To characterize further GRO-mediated inhibition of DNA replication, we used an in vitro assay based on replication of SV40 DNA. GROs were found to be capable of inhibiting DNA replication in the in vitro assay, and this activity was correlated to their antiproliferative effects. Furthermore, the effect of GROs on DNA replication in this assay was related to their inhibition of SV40 large T antigen helicase activity. The data presented suggest that the antiproliferative activity of GROs is a direct result of their inhibition of DNA replication, which may result from modulation of a replicative helicase activity.Oligonucleotides can recognize both nucleic acids and proteins with a high degree of specificity. This is a major reason why they have been widely investigated as potential therapeutic agents for cancer, viral infections, and inflammatory diseases. Oligonucleotides can achieve target recognition by sequence-specific interactions with nucleic acids or proteins such as in the antisense, antigene, or decoy approaches (1-4). Alternatively, target recognition can be due to the specific threedimensional structure of an oligonucleotide, as in the aptamer approach (5, 6). These aptameric oligonucleotides often contain secondary structure elements such as hairpins or G-quartets. The formation of G-quartet structures is also thought to contribute to non-antisense growth inhibitory effects of G-rich phosphodiester and phosphorothioate oligonucleotides (7-9).Recently, we reported (9) on a novel class of phosphodiester G-rich oligonucleotides (GROs) 1 that could strongly inhibit the in vitro proliferation of tumor cells derived from prostate, breast, and cervical carcinomas. The antiproliferative GROs were able to form stable secondary structures consistent with G-quartet format...

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“…This was followed by a longer, second phase in which the rate of unwinding was reduced 26-fold to 4(±3) bp s −1 ( Figure 5(b)). The reduced unwinding rate induced by adozelesin was accompanied by the appearance of stable intermediates that migrated just below the dsDNA substrate ( Figure 5(a), lanes [11][12][13][14][15][16][17]. The positions of migration of these unwinding intermediates in the gel were consistent from experiment to experiment, and the level of these intermediate species became more pronounced at increased molecular ratios of adozelesin to DNA (≥2885 drug molecules per DNA, data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…First, discrete-sized and stable unwinding intermediates were formed that migrated between the substrate and full-length ssDNA (indicated by region (iii)). The position of migration of these intermediates is different from those observed during the unwinding of χ°-DNA (compare Figure 5(a), lanes 10-18 with Figure 8, lanes [10][11][12][13][14][15][16][17][18]. Second, although the DNA substrate was unwound completely, formation of the anticipated χ-specific fragments did not occur.…”

Section: Under Catalytic Conditions Modification By Adozelesin Trapsmentioning

confidence: 86%

“…For example, daunorubicin was shown to potently inhibit DNA unwinding by Tag and mammalian helicase II, but affected DNA unwinding by the bacterial UvrD and Rep helicases only moderately. [9][10][11][12] Similarly, intercalating agents inhibit UvrD, whereas minor groove-binding agents do not. 9 In contrast, whereas minor groovebinding compounds are potent inhibitors of both the Bloom's and Werner's DNA helicases, intercalating agents do not inhibit these DNA helicases significantly.…”

Section: Introductionmentioning

confidence: 99%

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