Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells Through Lead Development

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 May 13

PMID 25965345

Citations 8

Authors

Ville Harma

Raisa Haavikko

Johannes Virtanen

Ilmari Ahonen

Hannu-Pekka Schukov

Sami Alakurtti

Enkhee Purev

Heiko Rischer

Jari Yli-Kauhaluoma

Vania M Moreira

Matthias Nees

Kirsi-Marja Oksman-Caldentey

Affiliations

Soon will be listed here.

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.

Citing Articles

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