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 (Corresponding Author), Kirsi-Marja Oksman-Caldentey (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

11 Citations (Scopus)

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 botulin 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 signalling 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 - 2015
MoE publication typeA1 Journal article-refereed

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

Cite this

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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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 botulin 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 signalling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.",
author = "Ville H{\"a}rm{\"a} and Raisa Haavikko and Johannes Virtanen and Ilmari Ahonen and Hannu-Pekka Schukov and Sami Alakurtti and Enkhee Purev and Heiko Rischer and Jari Yli-Kauhaluoma and Moreira, {V{\^a}nia M.} and Matthias Nees and Kirsi-Marja Oksman-Caldentey",
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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 (Corresponding Author); Oksman-Caldentey, Kirsi-Marja (Corresponding Author).

In: PLoS ONE, Vol. 10, No. 5, e0126111, 2015.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

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

Y1 - 2015

N2 - 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 botulin 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 signalling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.

AB - 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 botulin 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 signalling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.

U2 - 10.1371/journal.pone.0126111

DO - 10.1371/journal.pone.0126111

M3 - Article

VL - 10

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 5

M1 - e0126111

ER -