title: Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90.
abstract: Two new scalarane sesterterpenoids, 12β-(3'β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12β-(3'β-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 μg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70S6k, NFκB, Raf-1, p-GSK3β, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung, 944, Taiwan.|National Museum of Marine Biology &Aquarium, Pingtung 944, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.|Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors: Kuei-Hung
authors: KH
authors: Lai
authors: Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.|Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
authors: Yi-Chang
authors: YC
authors: Liu
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung, 944, Taiwan.|National Museum of Marine Biology &Aquarium, Pingtung 944, Taiwan.
authors: Jui-Hsin
authors: JH
authors: Su
authors: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 11566, Egypt.
authors: Mohamed
authors: M
authors: El-Shazly
authors: Division of Surgical Oncology, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors: Chih-Fung
authors: CF
authors: Wu
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung, 944, Taiwan.|National Museum of Marine Biology &Aquarium, Pingtung 944, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Ying-Chi
authors: YC
authors: Du
authors: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Yu-Ming
authors: YM
authors: Hsu
authors: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors: Juan-Cheng
authors: JC
authors: Yang
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung, 944, Taiwan.
authors: Ming-Kai
authors: MK
authors: Weng
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung, 944, Taiwan.|National Museum of Marine Biology &Aquarium, Pingtung 944, Taiwan.
authors: Chia-Hua
authors: CH
authors: Chou
authors: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.|Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
authors: Guan-Yu
authors: GY
authors: Chen
authors: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
authors: Yu-Cheng
authors: YC
authors: Chen
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung, 944, Taiwan.|National Museum of Marine Biology &Aquarium, Pingtung 944, Taiwan.
authors: Mei-Chin
authors: MC
authors: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D011161:Porifera / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D054830:Sesterterpenes / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous
chemical_list: D004224:Diterpenes; D018841:HSP90 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; D054830:Sesterterpenes; D004250:DNA Topoisomerases, Type II