Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α

Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shigetoshi; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki

doi:10.1016/j.bbrc.2006.11.021

Cited by 24 publications

(19 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dehydroaltenusin (17), isolated from A. tenuis, was found to be a specific inhibitor of eukaryotic DNA polymerase α to show its strong cytotoxic activity on tumor cells [45,78]. This compound also exhibited strong inhibitory activity on mammalian DNA polymerase α in vitro [79].…”

Section: Cytotoxic Activitymentioning

confidence: 99%

See 1 more Smart Citation

Natural Dibenzo-α-Pyrones and Their Bioactivities

Mao

Sun

et al. 2014

Molecules

View full text Add to dashboard Cite

Natural dibenzo-α-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-α-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-α-pyrones have been reported in the past few decades. This mini-review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-α-pyrones are also discussed.

show abstract

Section: Cytotoxic Activitymentioning

confidence: 99%

“…Some Alternaria-derived dibenzo-α-pyrones were approved as the host-specific phytotoxins including altenuene (1), alternariol (10), alternariol 9-methyl ether (11), alternuisol (15), and dehydroaltenusin (17) [9,10,37,39,41,45].…”

Section: Phytotoxicitymentioning

confidence: 99%

Natural Dibenzo-α-Pyrones and Their Bioactivities

Mao

Sun

et al. 2014

Molecules

View full text Add to dashboard Cite

show abstract

“…The human DNA polymerase  (pol ) catalyzes the very first steps in DNA replication and therefore is an interesting target. Recently, selective non-nucleoside inhibitors of pol  such as dehydroaltenusin 5 , glycolipids from green tea and spinach, and acyl-catechins [6][7][8][9] have been described, strengthening the relevance of this target. In fact, some nucleoside pol  inhibitors are already used systemically for leukemia (cytarabine, fludarabine 10 ) and pancreatic carcinoma (gemcitabine).…”

Section: Introductionmentioning

confidence: 99%

Human polymerase α inhibitors for skin tumors. Part 2. Modeling, synthesis and influence on normal and transformed keratinocytes of new thymidine and purine derivatives

Höltje

Richartz

Zdrazil

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

Journal of Enzyme Inhibition and Medicinal Chemistry, 2010; 25(2): 250-265 Abstract Recently, the three-dimensional structure of the active site of human DNA polymerase α (pol α) was proposed based on the application of molecular modeling methods and molecular dynamic simulations. The modeled structure of the enzyme was used for docking selective inhibitors (nucleotide analogs and the non-nucleoside inhibitor aphidicolin) in its active site in order to design new drugs for actinic keratosis and squamous cell carcinoma (SCC). The resulting complexes explained the geometrical and physicochemical interactions of the inhibitors with the amino acid residues involved in binding to the catalytic site, and offered insight into the experimentally derived binding data. The proposed structures were synthesized and tested in vitro for their influence on human keratinocytes and relevant tumor cell lines. Effects were compared to aphidicolin which inhibits pol α in a non-competitive manner, as well as to diclofenac and 5-fluorouracil, both approved for therapy of actinic keratosis. Here we describe three new nucleoside analogs inhibiting keratinocyte proliferation by inhibiting DNA synthesis and inducing apoptosis and necrosis. Thus, the combination of modeling studies and in vitro tests should allow the derivation of new drug candidates for the therapy of skin tumors, given that the agents are not relevant substrates of nucleotide transporters expressed by skin cancer cells. Kinases for nucleoside activation were detected, too, corresponding with the observed effects of nucleoside analogs. R E S E A R C H A R T I C L E Keywords: Human DNA polymerase; polymerase inhibitors; keratinocytes; molecular dynamic simulations; nucleoside analogs; kinases; nucleoside transportersAbbreviations: 5-FU, 5-fluorouracil; annexin V-FITC, rh annexin V labeled with fluorescein isothiocyanate; ara-G (nelarabine), 2-amino-9--d-arabinofuranosyl-6-methoxy-9H-purine; ATCC, American Type Culture Collection; dCK, deoxycytidine kinase; dGK, deoxyguanosine kinase; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethylsulfoxide; dNTP, deoxynucleoside triphosphate; EDTA, ethylene diamine tetraacetic acid; FCS, fetal calf serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HaCaT, spontaneously transformed human keratinocyte cell line; hENT-1, human equilibrative nucleoside transporter; KBM, keratinocyte basal medium; KGM, keratinocyte growth medium; MCF-7, human breast adenocarcinoma cell line; MRP, multidrug resistance protein; MTT, methylthiazolyldiphenyltetrazolium bromide; NHK, normal human keratinocytes; NRU, neutral red uptake; PBS, phosphate buffered saline, pH 7.4; PI, propidium iodide; RPMI, Roosevelt Park Memorial Institute; RT-PCR, reverse transcriptase polymerase chain reaction; SCC, squamous cell carcinoma; TK-1, thymidine kinase; TPace, thymidine phosphorylase; TP, triphosphate

show abstract

“…HeLa cells (1 × 10 7 cells/mouse) were subcutaneously injected into the lower abdominal region of the mice, and the animal model was established as previously described [12], with some modifications. The mice were randomly divided into 4 groups: control group (normal saline), low-dose PDC group (10 mg/mL/day), medium-dose PDC group (20 mg/mL/day) and the high-dose PDC group (40 mg/mL/day).…”

Section: Animal Model and Administrationmentioning

confidence: 99%