In Vivo Antitumor Activity of Clitocine, an Exocyclic Amino Nucleoside Isolated from <i>Lepista inversa</i>

Fortin, Helene; Tomasi, Sophie; Delcros, Jean‐Guy; Bansard, Jean‐Yves; Boustié, Joël

doi:10.1002/cmdc.200500029

Cited by 24 publications

(7 citation statements)

References 16 publications

(25 reference statements)

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“…Clitocine, a nucleoside firstly isolated from the mushroom Clitocybe inversa in 1980s, was found to be a substrate and inhibitor of adenosine kinase [25]. Recent years, clitocine was reported to exert an anti-tumor effect in varies cancer cell lines such as Hela and MCF-7 cells, and many derivatives of this compound were also synthesized and examined for their biological properties [25], [26], [27], [28]. In the present study, we found that clitocine reverse the P-gp associated multidrug resistance in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Clitocine Reversal of P-Glycoprotein Associated Multi-Drug Resistance through Down-Regulation of Transcription Factor NF-κB in R-HepG2 Cell Line

Sun

Yeung

et al. 2012

PLoS ONE

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Multidrug resistance(MDR)is one of the major reasons for failure in cancer chemotherapy and its suppression may increase the efficacy of therapy. The human multidrug resistance 1 (MDR1) gene encodes the plasma membrane P-glycoprotein (P-gp) that pumps various anti-cancer agents out of the cancer cell. R-HepG2 and MES-SA/Dx5 cells are doxorubicin induced P-gp over-expressed MDR sublines of human hepatocellular carcinoma HepG2 cells and human uterine carcinoma MES-SA cells respectively. Herein, we observed that clitocine, a natural compound extracted from Leucopaxillus giganteus, presented similar cytotoxicity in multidrug resistant cell lines compared with their parental cell lines and significantly suppressed the expression of P-gp in R-HepG2 and MES-SA/Dx5 cells. Further study showed that the clitocine increased the sensitivity and intracellular accumulation of doxorubicin in R-HepG2 cells accompanying down-regulated MDR1 mRNA level and promoter activity, indicating the reversal effect of MDR by clitocine. A 5′-serial truncation analysis of the MDR1 promoter defined a region from position −450 to −193 to be critical for clitocine suppression of MDR1. Mutation of a consensus NF-κB binding site in the defined region and overexpression of NF-κB p65 could offset the suppression effect of clitocine on MDR1 promoter. By immunohistochemistry, clitocine was confirmed to suppress the protein levels of both P-gp and NF-κB p65 in R-HepG2 cells and tumors. Clitocine also inhibited the expression of NF-κB p65 in MES-SA/Dx5. More importantly, clitocine could suppress the NF-κB activation even in presence of doxorubicin. Taken together; our results suggested that clitocine could reverse P-gp associated MDR via down-regulation of NF-κB.

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Section: Introductionmentioning

confidence: 99%

Clitocine Reversal of P-Glycoprotein Associated Multi-Drug Resistance through Down-Regulation of Transcription Factor NF-κB in R-HepG2 Cell Line

Sun

Yeung

et al. 2012

PLoS ONE

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“…For example illudin, a tricyclic sesquiter-pene from Omphalotus olearius, has served as the lead structure for the semisynthetic drug irofulven, which is currently in preclinical and clinical trials due to its effects against cancer-related kinases and apoptotic activity against a range of tumors (Baekelandt 2002). Cordycepin, isolated from several Cordyceps species, has shown an apoptotic effect on various cancer cell lines ( Jin et al 2008, Wu et al 2007 while the cytotoxicity of Lepista species has been attributed to the clitoclines (Fortin et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Ethanolic and aqueous extracts derived from Australian fungi inhibit cancer cell growth in vitro

Beattie¹,

Ulrich

Grice

et al. 2011

Mycologia

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Fifteen Australian macrofungi were investigated for cytotoxic activity. Ethanol, cold and hot water extracts of each species were screened for cytotoxic activity against normal mouse fibroblast cells (NIH/3T3), healthy human epithelial kidney cells (HEK-293), four cancer cell lines, gastric adenocarcinoma cells (AGS), two mammary gland adenocarcinoma cells (MDA-MB-231, MCF7) and colorectal adenocarcinoma cells (HT-29) with a validated MTT assay. Most extracts derived from Omphalotus nidiformis, Cordyceps cranstounii and Cordyceps gunnii demonstrated significant cytotoxic activity toward a variety of cancer cell lines. In contrast only some extracts from Coprinus comatus, Cordyceps hawkesii, Hypholoma fasciculare, Lepista nuda, Leratiomyces ceres and Ophiocordyceps robertsii displayed significant cytotoxic activity, which was usually selective for only one or two cancer cell lines tested. The least cytotoxic species evaluated in this study were Agaricus bitorquis, Coprinopsis atrametaria, Psathyrella asperospora, Russula clelandii, Tricholoma sp. AU2 and Xerula mundroola.

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“…Fortin and coworkers isolated clitocine fractions in various a/b ratios from Lepista inverse -the pure b-anomer clitocine, mixture A (a/b ¼ 60 : 40), and mixture B (a/b ¼ 20 : 80) [7]. Interestingly, all of these fractions exhibited similar cytotoxic activities, with IC 50 values ranging from 20.5 to 42 nM in murine cancer cell lines (3LL and L1210), and from 185 to 578 nM in human cancer cell lines (DU145, K-562, MCF7, and U251).…”

Section: Biological Activitymentioning

confidence: 99%

Clitocine and Its Analogues

Shin¹,

Min²

2008

Modified Nucleosides

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Guided by the insecticidal activity against the agricultural pest insect Pectinophora gossypiella, Kubo and Kim isolated clitocine (1a) [1], along with adenosine, from Clitocybe inversa, a medium-sized, buff-colored mushroom found in western North America. The NMR spectral data for clitocine was found to be very similar to that of adenosine, with the exception of the absence of the C-8 carbon peak of adenosine, while the low chemical shift of the 4-NH proton suggested strong hydrogen bonding between the 5-NO 2 and 4-NH groups. Later, Moss and coworkers [2] confirmed its structure through X-ray crystallographic analysis: as postulated earlier by Kubo et al., the entire aglycone moiety resembles a tricyclic ring system as a result of the hydrogen bonding between the 4-NH and 6-NH protons and the NO 2 group. SynthesisThe interesting biological activity of clitocine, together with its biogenetically close relationship to adenosine, triggered an immediate attempt to synthesize the molecule de novo. Two years after its initial isolation, two independent syntheses have now been completed. The first synthesis [3] is based upon the condensation of 2,3,5-tribenzoylribofuranosylamine (2) with 4,6-dichloro-5-nitropyrimidine (3) in the presence of a base to give a mixture of the a-and b-anomers in a 7 : 1 ratio (Scheme 22.1), although the yield (19%) is relatively poor. Deprotection of the benzoate group of 4 using a methanolic ammonia solution produced clitocine with a 71% yield. In order to improve the efficiency and reproducibility of the coupling reaction, an acetonideprotected amino sugar (5) was employed for the coupling reaction with 4-chloro-5-Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

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In Vivo Antitumor Activity of Clitocine, an Exocyclic Amino Nucleoside Isolated from Lepista inversa

Cited by 24 publications

References 16 publications

Clitocine Reversal of P-Glycoprotein Associated Multi-Drug Resistance through Down-Regulation of Transcription Factor NF-κB in R-HepG2 Cell Line

Clitocine Reversal of P-Glycoprotein Associated Multi-Drug Resistance through Down-Regulation of Transcription Factor NF-κB in R-HepG2 Cell Line

Ethanolic and aqueous extracts derived from Australian fungi inhibit cancer cell growth in vitro

Clitocine and Its Analogues

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