Molecular Determinants of Site-specific Inhibition of Human DNA Topoisomerase I by Fagaronine and Ethoxidine

Fleury, Fabrice; Sukhanova, Alyona; Ianoul, Anatoli; Devy, Jérôme; Kudelina, Irina A.; Duval, Olivier; Alix, Alain J. P.; Jardillier, Jean‐Claude; Nabiev, Igor

doi:10.1074/jbc.275.5.3501

Cited by 57 publications

(31 citation statements)

References 30 publications

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“…Natural benzo[c]phenanthridine alkaloids such as nitidine and fagaronine were known for their antileukemic activities as early as in the 1970s (2,3). Fagaronine has been reported to be a DNA binding agent and inhibitor of topoisomerases (4,5). Nitidine has also been reported to be a topoisomerase I inhibitor (6).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Guo

Liu

Nishikawa

et al. 2007

Molecular Cancer Therapeutics

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NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that has recently entered clinical trials as an antitumor compound, based on impressive activities in preclinical models. The present investigations were directed at determining the mechanism of action of this agent. NK314 induced significant G 2 cell cycle arrest in several cell lines, independent of p53 status, suggesting the existence of a common mechanism of checkpoint activation. The Chk1-Cdc25C-Cdk1 G 2 checkpoint pathway was activated in response to 100 nmol/L NK314 in ML-1 human acute myeloid leukemia cells. This was associated with the phosphorylation of the histone variant H2AX, an action that was predominant in the G 2 population, suggesting that double-strand DNA breaks caused cells to activate the checkpoint pathway. Double-strand DNA breaks were visualized as chromosomal aberrations when the G 2 checkpoint was abrogated by 7-hydroxystaurosporine. In vitro assays showed that NK314 inhibited the ability of topoisomerase IIA to relax supercoiled DNA and trapped topoisomerase IIA in its cleavage complex intermediate. CEM/VM1 cells, which are resistant to etoposide due to mutations in topoisomerase IIA, were cross-resistant to NK314. However, CEM/C2 cells, which are resistant to camptothecin due to mutations in topoisomerase I, retained sensitivity. These findings support the conclusion that the major mechanism of NK314 is to inhibit topoisomerase IIA, an action that leads to the generation of double-strand DNA breaks, which activate the G 2 DNA damage checkpoint pathway. [Mol Cancer Ther 2007;6(5):1501 -8]

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Section: Introductionmentioning

confidence: 99%

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Guo

Liu

Nishikawa

et al. 2007

Molecular Cancer Therapeutics

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“…Recently, compounds with phenathroline skeleton have been synthesized and biologically evaluated [11][12][13][14][15] as analogues of benzo[c]phenanthridine alkaloids (e.g. nitidine, fagaronine, sanguinarine) that attracted attention due to their interesting biological properties [16][17][18][19] . Compared to 1,10-phenanthroline that has been widely studied both for synthesis and applications, 4,7-phenanthroline received much less interest due to difficulties in its synthesis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Matarneh

Mangalagiu

Shova³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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A study concerning design, synthesis, structure and in vitro antimycobacterial and anticancer evaluation of new fused derivatives with pyrrolo[2,1-c] [4,7]phenanthroline skeleton is described. The strategy adopted for synthesis involves a [3 + 2] dipolar cycloaddition of several in situ generated 4,7-phenanthrolin-4-ium ylides to different substituted alkynes and alkenes. Stereo-and regiochemistry of cycloaddition reactions were discussed. The structure of the new compounds was proven unambiguously, single-crystal X-ray diffraction studies including. The antimycobacterial and anticancer activity of a selection of new synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv under aerobic conditions and 60 human tumour cell line panel, respectively. Five of the tested compounds possess a moderate antimycobacterial activity, while two of the compounds have a significant antitumor activity against renal cancer and breast cancer.

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“…Fagaronine leads to the disruption of replication in rapidly growing cancer, thus affecting their growth. Reverse transcriptases are also inhibited by fagaronine (Fleury et al, 2000).…”

Section: Fagara Zanthoxyloides Lmentioning

confidence: 99%

Phytochemical importance of medicinal plants as potential sources of anticancer agents

Raina¹,

Soni²,

Jauhari³

et al. 2014

Turk J Bot

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The diverse and magnificent plant kingdom of the world is widely known for its medicinal importance. The potential medicinal properties of plant species have contributed significantly in the development of various herbal therapies for a number of diseases across the globe. The benefits of herbal medicine over allopathic medicine have helped medicinal plants to regain their importance in the field of health and medicine. Cancer is one of the major health problems that have widely affected the world's population. There is a great need to combat this disease with better and more effective medication as compared to existing therapies. A vast number of medicinal plants are known to have biochemical constituents with anticancer properties. The chemical metabolites of natural origin that possess anticancer properties can serve as potential lead compounds in drug designing. This association of medicinal plants and cancer needs further research and experimentation in order to develop and design anticancer drugs. The present review is an effort to compile information on some of the geographically diverse and important medicinal plants that possess anticancer activity.

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Molecular Determinants of Site-specific Inhibition of Human DNA Topoisomerase I by Fagaronine and Ethoxidine

Cited by 57 publications

References 30 publications

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Phytochemical importance of medicinal plants as potential sources of anticancer agents

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