(−)-Xanthatin Selectively Induces GADD45γ and Stimulates Caspase-Independent Cell Death in Human Breast Cancer MDA-MB-231 Cells

• Published in: Chemical research in toxicology 2011-06, Vol.24 (6), p.855-865
• Main 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
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Caspases - metabolism; Cell Cycle - drug effects; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; DNA Topoisomerases, Type I - metabolism; Female; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; GADD45 Proteins; Gene Expression Regulation, Neoplastic - drug effects; Heme Oxygenase-1 - genetics; Humans; Interleukin-18 - genetics; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Signal Transduction - drug effects; Up-Regulation - drug effects; Xanthium - chemistry
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx200046s

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.