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Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Natl Dong Hwa Univ, Grad Inst Marine Biol, Pingtung 944, Taiwan.;Natl Museum Marine Biol Aquarium, Pingtung 944, Taiwan.;Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 807, Taiwan..
Kaohsiung Med Univ Hosp, Dept Internal Med, Div Hematol Oncol, Kaohsiung 807, Taiwan.;Kaohsiung Med Univ, Coll Med, Fac Med, Dept Internal Med, Kaohsiung 807, Taiwan..
Natl Dong Hwa Univ, Grad Inst Marine Biol, Pingtung 944, Taiwan.;Natl Museum Marine Biol Aquarium, Pingtung 944, Taiwan..
Ain Shams Univ, Dept Pharmacognosy & Nat Prod Chem, Fac Pharm, Org African Unity St, Cairo 11566, Egypt..
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 36170Article in journal (Refereed) Published
Abstract [en]

Two new scalarane sesterterpenoids, 12 beta-(3'beta-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12 beta-(3'beta-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 mu g/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase II alpha 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, p70(S6k), NF kappa B, Raf-1, p-GSK3 beta, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF1 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.

Place, publisher, year, edition, pages
2016. Vol. 6, 36170
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Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
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URN: urn:nbn:se:uu:diva-308635DOI: 10.1038/srep36170ISI: 000386462100001PubMedID: 27796344OAI: oai:DiVA.org:uu-308635DiVA: diva2:1050832
Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2016-11-30Bibliographically approved

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