Optimization of invasion-specific effects of betulin derivatives on prostate cancer cells through lead development

Ville Härmä, Raisa Haavikko, Johannes Virtanen, Ilmari Ahonen, Hannu-Pekka Schukov, Sami Alakurtti, Enkhee Purev, Heiko Rischer, Jari Yli-Kauhaluoma, Vânia M Moreira, Matthias Nees, Kirsi-Marja Oksman-Caldentey

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere0126111
Number of pages22
JournalPLOS One
Volume10
Issue number5
DOIs
Publication statusPublished - 12 May 2015

Fingerprint

betulin
prostatic neoplasms
Prostatic Neoplasms
chemical derivatives
Castration
Cells
cell lines
castration
Derivatives
Cell Line
Cell Movement
cytotoxicity
Abietane Diterpenes
Organoids
Cytotoxicity
cell invasion
Growth
androgens
microfilaments
Actin Cytoskeleton

Keywords

  • androgens
  • triterpenes
  • cell proliferation

Cite this

Härmä, V., Haavikko, R., Virtanen, J., Ahonen, I., Schukov, H-P., Alakurtti, S., ... Oksman-Caldentey, K-M. (2015). Optimization of invasion-specific effects of betulin derivatives on prostate cancer cells through lead development. PLOS One, 10(5), [e0126111]. https://doi.org/10.1371/journal.pone.0126111
Härmä, Ville ; Haavikko, Raisa ; Virtanen, Johannes ; Ahonen, Ilmari ; Schukov, Hannu-Pekka ; Alakurtti, Sami ; Purev, Enkhee ; Rischer, Heiko ; Yli-Kauhaluoma, Jari ; Moreira, Vânia M ; Nees, Matthias ; Oksman-Caldentey, Kirsi-Marja. / Optimization of invasion-specific effects of betulin derivatives on prostate cancer cells through lead development. In: PLOS One. 2015 ; Vol. 10, No. 5.
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Härmä, V, Haavikko, R, Virtanen, J, Ahonen, I, Schukov, H-P, Alakurtti, S, Purev, E, Rischer, H, Yli-Kauhaluoma, J, Moreira, VM, Nees, M & Oksman-Caldentey, K-M 2015, 'Optimization of invasion-specific effects of betulin derivatives on prostate cancer cells through lead development', PLOS One, vol. 10, no. 5, e0126111. https://doi.org/10.1371/journal.pone.0126111

Optimization of invasion-specific effects of betulin derivatives on prostate cancer cells through lead development. / Härmä, Ville; Haavikko, Raisa; Virtanen, Johannes; Ahonen, Ilmari; Schukov, Hannu-Pekka; Alakurtti, Sami; Purev, Enkhee; Rischer, Heiko; Yli-Kauhaluoma, Jari; Moreira, Vânia M; Nees, Matthias; Oksman-Caldentey, Kirsi-Marja.

In: PLOS One, Vol. 10, No. 5, e0126111, 12.05.2015.

Research output: Contribution to journalArticle

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T1 - Optimization of invasion-specific effects of betulin derivatives on prostate cancer cells through lead development

AU - Härmä, Ville

AU - Haavikko, Raisa

AU - Virtanen, Johannes

AU - Ahonen, Ilmari

AU - Schukov, Hannu-Pekka

AU - Alakurtti, Sami

AU - Purev, Enkhee

AU - Rischer, Heiko

AU - Yli-Kauhaluoma, Jari

AU - Moreira, Vânia M

AU - Nees, Matthias

AU - Oksman-Caldentey, Kirsi-Marja

PY - 2015/5/12

Y1 - 2015/5/12

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KW - androgens

KW - triterpenes

KW - cell proliferation

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