(-)-Xanthatin induces the prolonged expression of C-fos through an N-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells

Shuso Takeda, Hajime Nishimura, Kuniyoshi Koyachi, Kenji Matsumoto, Kazutaka Yoshida, Yoshiko Okamoto, Toshiaki Amamoto, Mitsuru Shindo, Hironori Aramaki

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12 Citations (Scopus)

Abstract

We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anticancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger antiproliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.

Original languageEnglish
Pages (from-to)547-557
Number of pages11
JournalJournal of Toxicological Sciences
Volume38
Issue number4
DOIs
Publication statusPublished - Aug 2013

All Science Journal Classification (ASJC) codes

  • Toxicology

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