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Antimitotic actions of a novel analog of the fungal metabolite palmarumycin CP<inf>1</inf>

Lazo, JS and Tamura, K and Vogt, A and Jung, JK and Rodriguez, S and Balachandran, R and Day, BW and Wipf, P (2001) Antimitotic actions of a novel analog of the fungal metabolite palmarumycin CP<inf>1</inf>. Journal of Pharmacology and Experimental Therapeutics, 296 (2). 364 - 371. ISSN 0022-3565

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Abstract

The pentacyclic palmarumycins are structurally unique natural products with both antifungal and antibacterial activities but their antineoplastic effects are not well established. We have examined their antiproliferative actions against tumor cells using a temperature-sensitive tsFT210 mouse mammary carcinoma cell line and found that a novel palmarumycin analog, [8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4- spiro-2′-naphtho [1″,8″-de][1′,3′][dioxin] or SR-7, prominently blocked mammalian cell cycle transition in G2/M but not in G1 phase. We found no evidence for inhibition of the critical mitosis-controlling cyclin-dependent kinase Cdk1, or its regulator, the dual specificity phosphatase Cdc25. Moreover, Cdk1 was hypophosphorylated and not directly inhibited by SR-7. SR-7 also failed in vitro to hypernucleate bovine tubulin, did not compete with colchicine for tubulin binding, and only modestly blocked GTP-induced assembly. In addition, SR-7 caused almost equal inhibition of paclitaxel-sensitive and -resistant cell growth. Moreover, unlike benchmark tubulin-disrupting agents, SR-7 did not cause hyperphosphorylation of the antiapoptotic protein Bcl-2. Thus, SR-7 represents a novel chemical structure that can inhibit G2/M transition by a mechanism that appears to be independent of marked tubulin disruption.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lazo, JSlazo@pitt.eduLAZO
Tamura, K
Vogt, A
Jung, JK
Rodriguez, S
Balachandran, R
Day, BW
Wipf, Ppwipf@pitt.eduPWIPF
Date: 14 February 2001
Date Type: Publication
Journal or Publication Title: Journal of Pharmacology and Experimental Therapeutics
Volume: 296
Number: 2
Page Range: 364 - 371
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-3565
MeSH Headings: Animals; Antineoplastic Agents--pharmacology; Binding, Competitive--drug effects; Blotting, Western; Breast Neoplasms--metabolism; Breast Neoplasms--pathology; Cell Division--drug effects; Colchicine--metabolism; Cyclin-Dependent Kinases--metabolism; Dioxanes--pharmacology; Female; Fibroblasts--drug effects; Flow Cytometry; Humans; Mice; Naphthalenes; Phosphoric Monoester Hydrolases--metabolism; Phosphorylation; Proto-Oncogene Proteins c-bcl-2--metabolism; Receptors, Estrogen--drug effects; Spiro Compounds--pharmacology; Tubulin--metabolism; Tumor Cells, Cultured; Tumor Suppressor Protein p53--metabolism
PubMed ID: 11160619
Date Deposited: 14 Feb 2014 17:03
Last Modified: 23 Jun 2018 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/20539

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