Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium

Utpal K. Karmakar, Naoki Ishikawa, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 μM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 μM.

Original languageEnglish
Pages (from-to)4746-4754
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number15
DOIs
Publication statusPublished - 2015 Jul 23
Externally publishedYes

Keywords

  • Asteraceae
  • Sesquiterpenes
  • TRAIL-resistance
  • Xanthium strumarium

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Karmakar, U. K., Ishikawa, N., Toume, K., Arai, M. A., Sadhu, S. K., Ahmed, F., & Ishibashi, M. (2015). Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium. Bioorganic and Medicinal Chemistry, 23(15), 4746-4754. https://doi.org/10.1016/j.bmc.2015.05.044