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(--)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells.

Authors
  • Takeda, Shuso
  • Matsuo, Kazumasa
  • Yaji, Kentaro
  • Okajima-Miyazaki, Shunsuke
  • Harada, Mari
  • Miyoshi, Hiroko
  • Okamoto, Yoshiko
  • Amamoto, Toshiaki
  • Shindo, Mitsuru
  • Omiecinski, Curtis J
  • Aramaki, Hironori
Type
Published Article
Journal
Chemical Research in Toxicology
Publisher
American Chemical Society
Publication Date
Jun 20, 2011
Volume
24
Issue
6
Pages
855–865
Identifiers
DOI: 10.1021/tx200046s
PMID: 21568272
Source
Medline
License
Unknown

Abstract

exo-Methylene lactone group-containing compounds, such as (--)-xanthatin, are present in a large variety of biologically active natural products, including extracts of Xanthium strumarium (Cocklebur). These substances are reported to possess diverse functional activities, exhibiting anti-inflammatory, antimalarial, and anticancer potential. In this study, we synthesized six structurally related xanthanolides containing exo-methylene lactone moieties, including (--)-xanthatin and (+)-8-epi-xanthatin, and examined the effects of these chemically defined substances on the highly aggressive and farnesyltransferase inhibitor (FTI)-resistant MDA-MB-231 cancer cell line. The results obtained demonstrate that (--)-xanthatin was a highly effective inhibitor of MDA-MB-231 cell growth, inducing caspase-independent cell death, and that these effects were independent of FTase inhibition. Further, our results show that among the GADD45 isoforms, GADD45γ was selectively induced by (--)-xanthatin and that GADD45γ-primed JNK and p38 signaling pathways are, at least in part, involved in mediating the growth inhibition and potential anticancer activities of this agent. Given that GADD45γ is becoming increasingly recognized for its tumor suppressor function, the results presented here suggest the novel possibility that (--)-xanthatin may have therapeutic value as a selective inducer of GADD45γ in human cancer cells, in particular in FTI-resistant aggressive breast cancers.

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