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Updated: Mar 29, 2026
Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
Targeting Phosphoinositide 3-Kinase to Reduce the Progression of Ovarian Cancer Cells in a 3D Collagen Model
Alexandria B Tino1, Peter H Sykes1,2, Gabi U Dachs3
1Gynaecological Cancer Research Group, Department of Obstetrics and Gynaecology, University of Otago Christchurch, Christchurch 8011, New Zealand.
Abstract:
Ovarian cancer remains a major cause of mortality in women aged 74 years and under. Dysregulation of the PI3K/AKT/mTOR and NFκB signaling pathways has been associated with poor outcomes and treatment resistance. This study evaluated three potential anticancer agents targeting these pathways: buparlisib (a pan-PI3K/mTORC1 inhibitor), SN32976 (a PI3K p110α inhibitor), and pterostilbene (a resveratrol analogue that downregulates PI3K/AKT and NFκB signaling). Their efficacy was tested in 3D collagen models of ovarian cancer, using SKOV3 and OVCAR8 cell lines, activated by tumor necrosis factor-alpha (TNFα) and lysophosphatidic acid (LPA). Using concentrations derived from 2D assays, viability, collagen gel sizes, secretion of interleukin 6/8 (IL-6/8) and signal pathway proteins were analyzed. All compounds were less effective in 3D models than in 2D cultures, with high cell viability maintained. TNFα and LPA did not significantly alter drug sensitivity, and collagen gel contraction was largely unaffected. While the compounds did not consistently change signaling protein levels, they generally reduced secretion of pro-inflammatory cytokines IL-6 and IL-8. Growth in 3D collagen gels conferred drug resistance on OVCAR8 but not SKOV3 models. Overall, these findings provide preclinical support for further investigation of SN32976 and pterostilbene in ovarian cancer models.
Insights
Three agents targeting PI3K/AKT/mTOR and NFκB pathways showed limited efficacy in 3D ovarian cancer models. SN32976 and pterostilbene warrant further investigation for ovarian cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian cancer is a leading cause of mortality, often linked to PI3K/AKT/mTOR and NFκB pathway dysregulation.
- This dysregulation contributes to poor prognosis and resistance to therapies.
- Targeting these critical signaling pathways presents a therapeutic opportunity.
Purpose of the Study:
- To evaluate the preclinical efficacy of buparlisib, SN32976, and pterostilbene against ovarian cancer.
- To assess drug performance in advanced 3D collagen models compared to traditional 2D cultures.
- To investigate the impact of tumor necrosis factor-alpha (TNFα) and lysophosphatidic acid (LPA) on drug sensitivity.
Main Methods:
- Utilized SKOV3 and OVCAR8 ovarian cancer cell lines within 3D collagen matrices.
- Administered buparlisib (pan-PI3K/mTORC1 inhibitor), SN32976 (PI3K p110α inhibitor), and pterostilbene (downregulates PI3K/AKT and NFκB).
- Analyzed cell viability, collagen gel dimensions, IL-6/8 secretion, and signaling protein levels.
Main Results:
- All tested agents demonstrated reduced efficacy in 3D models compared to 2D cultures, with sustained cell viability.
- TNFα and LPA stimulation did not significantly alter drug sensitivity or collagen gel contraction.
- Compounds generally decreased pro-inflammatory IL-6 and IL-8 secretion, but signaling protein changes were inconsistent.
- OVCAR8 cells exhibited drug resistance in 3D models, unlike SKOV3 cells.
Conclusions:
- 3D collagen models confer resistance to tested agents in certain ovarian cancer cell lines (OVCAR8).
- SN32976 and pterostilbene show potential for further preclinical development in ovarian cancer.
- The study highlights the importance of 3D models for evaluating drug efficacy in complex tumor microenvironments.
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