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

Shuso Takeda, Kazumasa Matsuo, Kentaro Yaji, Shunsuke Okajima-Miyazaki, Mari Harada, Hiroko Miyoshi, Yoshiko Okamoto, Toshiaki Amamoto, Mitsuru Shindo, Curtis J. Omiecinski, Hironori Aramaki

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)855-865
Number of pages11
JournalChemical Research in Toxicology
Volume24
Issue number6
DOIs
Publication statusPublished - Jun 20 2011

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Cell death
Caspases
Cell Death
Breast Neoplasms
Farnesyltranstransferase
Xanthium
Cells
Antimalarials
Cell growth
Neoplasms
Biological Products
MAP Kinase Signaling System
Tumors
Growth
Protein Isoforms
Anti-Inflammatory Agents
Antineoplastic Agents
xanthatin
Cell Line
methylene-lactone

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

(-)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells. / Takeda, Shuso; Matsuo, Kazumasa; Yaji, Kentaro; Okajima-Miyazaki, Shunsuke; Harada, Mari; Miyoshi, Hiroko; Okamoto, Yoshiko; Amamoto, Toshiaki; Shindo, Mitsuru; Omiecinski, Curtis J.; Aramaki, Hironori.

In: Chemical Research in Toxicology, Vol. 24, No. 6, 20.06.2011, p. 855-865.

Research output: Contribution to journalArticle

Takeda, S, Matsuo, K, Yaji, K, Okajima-Miyazaki, S, Harada, M, Miyoshi, H, Okamoto, Y, Amamoto, T, Shindo, M, Omiecinski, CJ & Aramaki, H 2011, '(-)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells', Chemical Research in Toxicology, vol. 24, no. 6, pp. 855-865. https://doi.org/10.1021/tx200046s
Takeda, Shuso ; Matsuo, Kazumasa ; Yaji, Kentaro ; Okajima-Miyazaki, Shunsuke ; Harada, Mari ; Miyoshi, Hiroko ; Okamoto, Yoshiko ; Amamoto, Toshiaki ; Shindo, Mitsuru ; Omiecinski, Curtis J. ; Aramaki, Hironori. / (-)-Xanthatin selectively induces GADD45γ and stimulates caspase-independent cell death in human breast cancer MDA-MB-231 cells. In: Chemical Research in Toxicology. 2011 ; Vol. 24, No. 6. pp. 855-865.
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