Small Deletion and Insertion Mutations Induced by the Topoisomerase II Inhibitor Teniposide in CHO Cells and Comparison with Sites of Drug-stimulated DNA Cleavage in Vitro

1993 ◽  
Vol 229 (1) ◽  
pp. 52-66 ◽  
Author(s):  
Yi-Hong Han ◽  
M.J.Finley Austin ◽  
Yves Pommier ◽  
Lawrence F. Povirk
Keyword(s):  
Cho Cells ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Topoisomerase Ii Inhibitor ◽  
Small Deletion ◽  
Insertion Mutations

AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2034-2040 ◽  
Author(s):  
Jing Yang ◽  
Takayuki Ikezoe ◽  
Chie Nishioka ◽  
Taizo Tasaka ◽  
Ayuko Taniguchi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
Growth Arrest ◽  
Leukemia Cells ◽  
Aurora B ◽  
Thymidine Uptake ◽  
Aurora B Kinase ◽  
Aurora Kinases ◽  
Topoisomerase Ii Inhibitor

Abstract Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell-cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the antiproliferative activity of vincristine, a tubulin depolymerizing agent, and daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine and daunorubicin in a MOLM13 murine xenograft model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.

scholarly journals Site-specific DNA cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivatives

1992 ◽  
Vol 282 (3) ◽  
pp. 883-889 ◽  
Author(s):  
C A Austin ◽  
S Patel ◽  
K Ono ◽  
H Nakane ◽  
L M Fisher
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Complex Analysis ◽  
Antiviral Agents ◽  
Epigallocatechin Gallate ◽  
Tea Plant ◽  
Epicatechin Gallate ◽  
Pyrone Ring ◽  
Cleavable Complex

Four naturally occurring flavones (baicalein, quercetin, quercetagetin and myricetin) and two novel catechins [(-)-epicatechin gallate and (-)-epigallocatechin gallate, from the tea plant Camellia sinensis], which are known inhibitors of reverse transcriptase, were shown to induce mammalian topoisomerase II-dependent DNA-cleavage in vitro. The flavones differed from the catechins in causing unwinding of duplex DNA, but both classes of compound induced enzymic DNA breakage at the same sites on DNA. Moreover, the cleavage specificity was the same as that for the known intercalator 4′-(acridin-9-ylamino)methanesulphon-m-anisidide, suggesting that these agents trap the same cleavable complex. Analysis of some 30 flavonoid compounds allowed elucidation of the structure-function relationships for topoisomerase II-mediated DNA cleavage. For flavonoid inhibitors an unsaturated double bond between positions 2 and 3 of the pyrone ring and hydroxy groups at the 5, 7, 3′ and 4′ positions favoured efficient cleavage. Hydroxy substitutions could be tolerated at the 3, 6 and 5′ positions. Indeed, the absence of substituents at the 3′, 4′ and 5′ positions could be compensated by a hydroxy group at position 6 (baicalein). Similar requirements have been reported for flavonoid inhibitors of protein kinase C that act competitively with ATP, suggesting interaction with a conserved protein feature. Formation of the cleavable complex is a cytotoxic lesion that may contribute to the growth-inhibitory properties of flavones observed for three human tumour cell lines. These results are discussed in regard to the selectivity of antiviral agents.

scholarly journals The Antimalarial Drug Pyronaridine Inhibits Topoisomerase Ii In Breast Cancer Cells And Hinders Tumor Progression In-Vivo

2021 ◽  
Vol 08 ◽  
Author(s):  
Paulina J. Villanueva ◽  
Denisse A Gutierrez ◽  
Lisett Contreras ◽  
Karla Parra ◽  
Giulio Francia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Antimalarial Drug ◽  
Human Breast Cancer ◽  
Topoisomerase Ii ◽  
Human Breast ◽  
Topoisomerase Ii Inhibitor

Background: Breast cancer is the most frequently diagnosed cancer in women worldwide. Pyronaridine (PND), an antimalarial drug, was shown to exert anticancer activity on seventeen different human cancer cells, seven from female breast tissue. Additionally, PND induced apoptosis via mitochondrial depolarization, alteration of cell cycle progression, and DNA intercalation. However, the molecular target of PND in cells was not elucidated. Objective: Here, we have further investigated PND's mode of action by using transcriptome analysis. Preclinical studies were also performed to determine whether PND could affect tumor progression in a human breast cancer xenograft in mice. Moreover, we assessed the combined efficacy of PND with well-known anticancer drugs. Methods: Transcriptome analyses of PND-treated cancer cells were performed. Topoisomerase II activity was evaluated by an in vitro assay. In addition, daily oral administration of PND was given to mice with human breast cancer xenografts. The differential nuclear staining assay measured in-vitro cell toxicity. Results: The transcriptome signatures suggested that PND might act as a topoisomerase II inhibitor. Thus, topoisomerase inhibition assays were performed, providing evidence that PND is a bona fide topoisomerase II inhibitor. Also, in-vivo studies suggest that PND hinders tumor progression. Besides, combination studies of PND with anticancer drugs Cisplatin and Gemcitabine revealed higher cytotoxicity against cancer cells than individual drug administration. Conclusion: The findings provide evidence that PND is a topoisomerase II inhibitor and can hinder cancer progression in an animal model, further demonstrating PND's favorable characteristics as a repurposed anticancer drug.

scholarly journals In Vitro Activities of Gepotidacin (GSK2140944) and Other Antimicrobial Agents against Human Mycoplasmas and Ureaplasmas

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Ken B. Waites ◽  
Donna M. Crabb ◽  
Li Xiao ◽  
Lynn B. Duffy
Keyword(s):  
Topoisomerase Ii ◽  
Antimicrobial Agents ◽  
Ureaplasma Urealyticum ◽  
Mycoplasma Hominis ◽  
Mycoplasma Genitalium ◽  
Content Type ◽  
Topoisomerase Ii Inhibitor ◽  
Ureaplasma Parvum ◽  
Type Strains

ABSTRACTGepotidacin, a novel first-in-class triazaacenaphthylene topoisomerase II inhibitor, was tested against 85 type strains and clinical isolates ofMycoplasma pneumoniae,Mycoplasma hominis,Mycoplasma genitalium,Ureaplasma parvum, andUreaplasma urealyticumin comparison to levofloxacin, moxifloxacin, azithromycin or clindamycin, and tetracycline. Gepotidacin MIC90s (μg/ml) were 0.125 (M. pneumoniae), 0.032 (M. genitalium), 2 (M. hominis), and 8 (Ureaplasmaspecies). Gepotidacin activity was not affected by resistance to fluoroquinolones, tetracyclines, or macrolides in the strains tested. Gepotidacin merits further study for treating infections caused by these organisms.

scholarly journals Chromosome damage induced by DNA topoisomerase II inhibitors combined with g-radiation in vitro

1998 ◽  
Vol 21 (3) ◽  
pp. 407-417
Author(s):  
Maria Cristina P. Araújo ◽  
Francisca da Luz Dias ◽  
Andréa O. Cecchi ◽  
Lusânia M.G. Antunes ◽  
Catarina S. Takahashi
Keyword(s):  
Cho Cells ◽  
Topoisomerase Ii ◽  
Chinese Hamster ◽  
The Other ◽  
Additive Effects ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Topoisomerase Ii Inhibitors ◽  
Radiation Induced

Combined radiation and antineoplastic drug treatment have important applications in cancer therapy. In the present work, an evaluation was made of two known topoisomerase II inhibitors, doxorubicin (DXR) and mitoxantrone (MXN), with g-radiation. The effects of DXR or MXN on g-radiation-induced chromosome aberrations in Chinese hamster ovary (CHO) cells were analyzed. Two concentrations of each drug, 0.5 and 1.0 µg/ml DXR, and 0.02 and 0.04 µg/ml MXN, were applied in combination with two doses of g-radiation (20 and 40 cGy). A significant potentiating effect on chromosomal aberrations was observed in CHO cells exposed to 1.0 µg/ml DXR plus 40 cGy. In the other tests, the combination of g-radiation with DXR or MXN gave approximately additive effects. Reduced mitotic indices reflected higher toxicity of the drugs when combined with radiation.

scholarly journals Effect of ICRF-193, a novel DNA topoisomerase II inhibitor, on simian virus 40 DNA and chromosome replication in vitro.

1992 ◽  
Vol 12 (9) ◽  
pp. 4007-4014 ◽  
Author(s):  
Y Ishimi ◽  
R Ishida ◽  
T Andoh
Keyword(s):  
Molecular Weight ◽  
Dna Replication ◽  
Late Stage ◽  
Topoisomerase Ii ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Chromosome Replication ◽  
Topoisomerase Ii Inhibitor ◽  
Sv40 Dna

The effect of ICRF-193, a noncleavable-complex-forming topoisomerase II inhibitor, on simian virus 40 (SV40) DNA and SV40 chromosome replication was examined by using an in vitro replication system composed of HeLa cell extracts and SV40 T antigen. Unlike the topoisomerase inhibitors VP-16 and camptothecin, ICRF-193 had little effect on DNA chain elongation during SV40 DNA replication, but high-molecular-weight DNAs instead of segregated monomer DNAs accumulated as major products. Analysis of the high-molecular-weight DNAs by two-dimensional gel electrophoresis revealed that they consisted of catenated dimers and late Cairns-type DNAs. Incubation of the replicated DNA with topoisomerase II resulted in conversion of the catenated dimers to monomer DNAs. These results indicate that ICRF-193 induces accumulation of catenated dimers and late Cairns-type DNAs by blocking the decatenating and relaxing activities of topoisomerase II in the late stage of SV40 DNA replication. In contrast, DNA replication of SV40 chromosomes was severely blocked by ICRF-193 at the late stage, and no catenated dimers were synthesized. These results are consistent with the finding that topoisomerase II is required for unwinding of the final duplex DNA in the late stage of SV40 chromosome replication in vitro.

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