Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development
Ville Härmä1, Raisa Haavikko2, Johannes Virtanen1
1Industrial Biotechnology, VTT Technical Research Centre of Finland Ltd, Turku, Finland.
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.
Insights
Betulin derivatives show promise in combating prostate cancer by inhibiting invasion and proliferation. These compounds specifically target AKT signaling and actin cytoskeleton organization, offering a new therapeutic avenue for castration-resistant prostate cancer.
Area of Science:
- Pharmacology
- Oncology
- Cell Biology
Background:
- Prostate cancer, particularly castration-resistant forms, presents significant challenges due to its invasiveness and proliferation.
- Betulins and abietane derivatives are natural compounds with potential anti-cancer properties requiring systematic evaluation.
Purpose of the Study:
- To systematically evaluate the anti-invasive and anti-proliferative effects of betulins and abietane derivatives on prostate cancer models.
- To identify specific compounds and their mechanisms of action against advanced, castration-resistant prostate cancer.
Main Methods:
- Organotypic model systems and 2D/3D cell cultures (EP156T, LNCaP, PC-3) were used for compound screening.
- Phenotypic analyses assessed effects on cell cycle, mitosis, proliferation, cytotoxicity, motility, and invasion.
- Multiplex profiling identified compound targets by analyzing effects on 43 human protein kinases.
Main Results:
- A preliminary screen identified 25 betulin derivatives as most promising.
- These derivatives demonstrated specific anti-invasive properties in 3D models.
- Mechanism of action studies revealed inhibition of AKT signaling and disruption of actin cytoskeleton organization.
Conclusions:
- Betulin derivatives exhibit significant anti-invasive and anti-proliferative effects against castration-resistant prostate cancer.
- Specific inhibition of AKT signaling and actin cytoskeleton organization is the likely mechanism driving these anti-cancer effects.
- These findings support further development of betulin derivatives as targeted therapies for advanced prostate cancer.
