TRAIL selectively kills cancer cells without harming most normal cells. However, TRAIL resistance is a major problem for its therapeutic use. Developing a strategy to overcome resistance is crucial for the successful use of TRAIL as an antitumor agent. In our screening program of natural products that can abrogate TRAIL resistance, four germacranolides (1–4) were isolated from the aerial parts of Enhydra fluctuans. All compounds exhibited potent TRAIL-resistance overcoming activity against TRAIL-resistant human gastric adenocarcinoma (AGS) cells.
(a) AhmedF., IshibashiM. (2016) Bio-active natural products with TRAIL-resistance overcoming activity. Chemical and Pharmaceutical Bulletin, 64, 119–127; (b) Amarante-Mendes, GP, Griffith TS. (2015) Therapeutic applications of TRAIL receptor agonists in cancer and beyond. Pharmacology and Therapeutics, 155, 117–131.
2.
CamidgeD.R. (2007) The potential of death receptor 4- and 5-directed therapies in the treatment of lung cancer. Clinical Lung Cancer, 8, 413–419.
3.
BaritakiS., Huerta-YepezS., SakaiT., SpandidosD.A., BonavidaB. (2007) Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: Up-regulation of DR5 and inhibition of Yin Yang 1. Molecular Cancer Therapeutics, 6, 1387–1399.
4.
HorinakaM., YoshidaT., ShiraishiT., NakataS., WakadaM., NakanishiR., NishinoH., MatsuiH., SakaiT. (2005) Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene, 24, 7180–7189.
5.
KarmakarU.K., IshikawaN., ToumeK., AraiM.A., SadhuS.K., AhmedF., IshibashiM. (2015) Sesquiterpenes with TRAIL-resistance overcoming activity from Xanthium strumarium. Bioorganic and Medicinal Chemistry, 23, 4746–4754.
6.
(a) KarmakarU.K., IshikawaN., AraiM.A., AhmedF., KoyanoT., KowithayakornT., IshibashiM. (2016) Boesenberols, pimarane diterpenes with TRAIL-resistance overcoming activity from Boesenbergia pandurata. Journal of Natural Products, 79, 2075–2082; (b) Ali MR, Billah MM, Hassan MM, Dewan SMR, Al-Emran M. (2013) Enhydra fluctuans Lour: A review. Research Journal of Pharmaceutical Technology, 6, 927–929.
7.
(a) AliE., GhoshP.P., PakrashiS.C. (1972) Structure of enhydrine, fluctuadine and flutuanins. Tetrahedron, 28, 2285–2298; (b) Krishnaswamy NR, Ramji N. (1995) Sesquiterpene lactones from Enhydra fluctuans. Phytochemistry, 38, 433–435; (c) Sannigrahi S, Mazumder UK, Mondal A, Pal D, Mishra SL, Roy S. (2010) Flavonoids of Enhydra fluctuans exhibit anticancer activity against Ehrlich's ascites carcinoma in mice. Natural Product Communications, 5, 1239–1242; (d) Lin, F., Hasegawa M, Kodama O. (2003) Purification and identification of antimicrobial sesquiterpene lactones from yacon (Smallanthus sonchifolius) leaves. Bioscience Biotechnology Biochemistry, 67, 2154–2159; (e) Kreuger MR, Grootjans S, Biavatti MW, Vandenabeele P, D'Herde K. (2002) Sesquiterpene lactones as drugs with multiple targets in cancer treatment: focus on parthenolide. Anticancer Drugs, 23, 883–896; (f) Gao X, Lin CJ, Jia ZJ. (2007) Cytotoxic germacranolides and acyclic diterpenoides from the seeds of Carpesium triste. Journal of Natural Products, 70, 830–834.
