title: Mechanistic Study of Tetrahydrofuran- acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma.
abstract: For past three decades, numerous studies have elucidated the antiproliferative effects of acetogenins in hopes of developing a new class of clinical anticancer agents. However, clear and definitive action mechanisms of acetogenins were less clarified. In the present study, three tetrahydrofuran (THF)-containing acetogenins were found to have potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate-resistant counterparts. The THF-containing acetogenins induced G2/M phase arrest, mitochondrial damage and apoptosis, and increased cytosolic and mitochondrial Ca2+in NPCs. Microarray analysis of NPC-TW01 cells treated with squamostatin A, a non-adjacent bis-THF acetogenin, demonstrated an increased endoplasmic reticulum (ER)-stress response (ESR). Enhanced ESR in squamostatin A-treated cells was confirmed by real-time PCR, Western blot and shRNA gene knockdown experiments. Although our results showed that squamostatin A-induced ESR was independent of extracellular Ca2+, the presence of extracellular Ca2+enhanced the antiproliferative effect of acetogenins. In vivo analyses demonstrated that squamostatin A showed good pharmacokinetic properties and significantly retarded NPC tumor growth in the xenograft mouse model. Conclusively, our work demonstrates that acetogenins are effective and selective inducers of the ESR that can block NPC proliferation, and illustrate a previously unappreciated antitumor mechanism of acetogenins that is effective against nasopharyngeal malignancies.
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.
authors.forename: Shin-Hun
authors.initials: SH
authors.lastname: Juang
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan.
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Chiang
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.
authors.forename: Fong-Pin
authors.initials: FP
authors.lastname: Liang
authors.affiliation: Department of Pharmacy, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Hsiu-Hui
authors.initials: HH
authors.lastname: Chan
authors.affiliation: Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan.
authors.forename: Shih-Hao
authors.initials: SH
authors.lastname: Wang
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Department of Pharmacology, Obstetrics &Gynecology, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
authors.affiliation: Department of Chemistry, Vinh University, Vinh City, Nghean province, Vietnam.
authors.forename: Tran Dinh
authors.initials: TD
authors.lastname: Thang
authors.affiliation: Department of Chemistry, Vinh University, Vinh City, Nghean province, Vietnam.
authors.forename: Bui Thi Minh
authors.initials: BT
authors.lastname: Nguyet
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Department of Pharmacy, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
mesh_terms: D054378:Acetogenins / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005663:Furans / Q000737:chemistry*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D054378:Acetogenins; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans; D006360:Heat-Shock Proteins; C540771:squamostanin A; C018674:tetrahydrofuran; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1