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Title: Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning

Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo II{alpha} activity through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC{sub 50} of 0.9 {mu}M, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC{sub 50} of 9.6 {mu}M, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 {mu}M. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC{sub 50} about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damagemore » induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.« less
Authors:
 [1] ; ;  [1] ;  [2] ;  [3] ;  [4] ; ; ;  [1] ;  [1] ;  [5]
  1. Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan (China)
  2. (China)
  3. Department of Food Science, National Chiayi University, Chiayi, Taiwan (China)
  4. Institute of Chemistry, Academia Sinica, Taipei, Taiwan (China)
  5. (China), E-mail: sblin@ntu.edu.tw
Publication Date:
OSTI Identifier:
21077948
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 227; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2007.11.014; PII: S0041-008X(07)00516-9; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTINEOPLASTIC DRUGS; APOPTOSIS; BLOOD; DNA; DNA DAMAGES; INTRAPERITONEAL INJECTION; LACQUERS; LEUKEMIA; POISONING; RATS; TOXICITY; TRIOCTYLPHOSPHINE OXIDE