(-)-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

• Published in: Journal of toxicological sciences Vol. 38; no. 4; pp. 547 - 557
• Main Authors: Takeda, Shuso, Nishimura, Hajime, Koyachi, Kuniyoshi, Matsumoto, Kenji, Yoshida, Kazutaka, Okamoto, Yoshiko, Amamoto, Toshiaki, Shindo, Mitsuru, Aramaki, Hironori
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2013
• Subjects: (-)-Xanthatin; Acetylcysteine - pharmacology; Antigens, Neoplasm; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Fos; Cell Division - genetics; DNA Topoisomerases, Type II; DNA-Binding Proteins - antagonists & inhibitors; Etoposide - pharmacology; Female; Free Radical Scavengers - pharmacology; Furans - pharmacology; GADD45 Proteins; GADD45γ; Gene Expression Regulation, Neoplastic - drug effects; Genes, Tumor Suppressor - drug effects; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction - methods; ROS; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.38.547

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 anti-cancer 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 anti-proliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.