| Autor: |
Christensen SB; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark. soren.christensen@sund.ku.dk., Simonsen HT; Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Bld 223, 2800, Kgs. Lyngby, Denmark., Engedal N; Department of Tumor Biology, Institute for Cancer Research, University Hospital, Montebello, 0379, Oslo, Norway., Nissen P; Department of Molecular Biology and Genetics, Danish Research Institute of Translational Neuroscience - DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, Gustav Wieds Vej 10C, 8000, Aarhus C, Denmark., Møller JV; Department of Biomedicine, Aarhus University, Ole Worms Allé 3, Bld 1182, Room 114, 8000, Aarhus C, Denmark., Denmeade SR; Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Maryland, The Johns Hopkins University School of Medicine, Baltimore, The Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21231, USA., Isaacs JT; Department of Oncology, Prostate Cancer Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Maryland, The Johns Hopkins University School of Medicine, Baltimore, The Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21231, USA. |
| Abstrakt: |
Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. The pronounced cytotoxicity of thapsigargin is caused by highly selective inhibition of the intracellular sarco-endoplasmic Ca 2+ -ATPase (SERCA) situated on the membrane of the endo- or sarcoplasmic reticulum. Thapsigargin is selective to the SERCA pump and to a minor extent the secretory pathway Ca 2+ /Mn 2+ ATPase (SPCA) pump. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography. These results led to descriptions of the mechanism of action and kinetic properties of SERCA and other ATPases. Inhibition of SERCA depletes Ca 2+ from the sarco- and endoplasmic reticulum provoking the unfolded protein response, and thereby has enabled new studies on the mechanism of cell death. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production. Principles for prodrug development were used by conjugating a payload derived from thapsigargin with a hydrophilic peptide selectively cleaved by proteases in the tumor. Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen (PSMA) in the neovascular tissue of the tumors. Even though mipsagargin showed interesting clinical effects the results did not encourage funding and consequently the attempt to register the drug has been abandoned. In spite of this disappointing fact, the research performed to develop the drug has resulted in important scientific discoveries concerning the chemistry, biosynthesis and biochemistry of sesquiterpene lactones, the mechanism of action of ATPases including SERCA, mechanisms for cell death caused by the unfolded protein response, and the use of prodrugs for cancer-targeting cytotoxins. The presence of toxins in only some species belonging to Thapsia also led to a major revision of the taxonomy of the genus. |
