title: Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development.
abstract: The anti-invasive and anti-proliferative effects of betulins and abietane derivatives was systematically tested using an organotypic model system of advanced, castration-resistant prostate cancers. A preliminary screen of the initial set of 93 compounds was performed in two-dimensional (2D) growth conditions using non-transformed prostate epithelial cells (EP156T), an androgen-sensitive prostate cancer cell line (LNCaP), and the castration-resistant, highly invasive cell line PC-3. The 25 most promising compounds were all betulin derivatives. These were selected for a focused secondary screen in three-dimensional (3D) growth conditions, with the goal to identify the most effective and specific anti-invasive compounds. Additional sensitivity and cytotoxicity tests were then performed using an extended cell line panel. The effects of these compounds on cell cycle progression, mitosis, proliferation and unspecific cytotoxicity, versus their ability to specifically interfere with cell motility and tumor cell invasion was addressed. To identify potential mechanisms of action and likely compound targets, multiplex profiling of compound effects on a panel of 43 human protein kinases was performed. These target de-convolution studies, combined with the phenotypic analyses of multicellular organoids in 3D models, revealed specific inhibition of AKT signaling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.
authors.affiliation: Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Turku, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Härmä
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Raisa
authors.initials: R
authors.lastname: Haavikko
authors.affiliation: Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Turku, Finland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Virtanen
authors.affiliation: Turku Centre for Biotechnology BTK, University of Turku, Turku, Finland.
authors.forename: Ilmari
authors.initials: I
authors.lastname: Ahonen
authors.affiliation: University of Turku, Faculty of Medicine, Institute of Biomedicine, Turku, Finland.
authors.forename: Hannu-Pekka
authors.initials: HP
authors.lastname: Schukov
authors.affiliation: Process Chemistry and Environmental Engineering, VTT Technical Research Centre of Finland Ltd, Espoo, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Alakurtti
authors.affiliation: Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Turku, Finland; National University of Mongolia, Ulanbataar, Mongolia.
authors.forename: Enkhee
authors.initials: E
authors.lastname: Purev
authors.affiliation: Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Espoo, Finland.
authors.forename: Heiko
authors.initials: H
authors.lastname: Rischer
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Vânia M
authors.initials: VM
authors.lastname: Moreira
authors.affiliation: Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Turku, Finland; Turku Centre for Biotechnology BTK, University of Turku, Turku, Finland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
authors.affiliation: Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Espoo, Finland.
authors.forename: Kirsi-Marja
authors.initials: KM
authors.lastname: Oksman-Caldentey
mesh_terms: D000728:Androgens / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D000728:Androgens; D011494:Protein Kinases; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid