The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer
Open accessAbstract
BACKGROUND: Advanced endometrial cancer often shows resistance to clinical chemotherapy although potencies of anticancer drugs in vitro are promising. The disparity suggests that in vivo microenvironments are not recapitulated by in vitro models used for preclinical testing. However, spheroids replicate some important properties of tumours in vivo. Therefore, for the first time, we compared effects of doxorubicin and cisplatin on 3D multicellular structures and 2D cell monolayers of endometrial cancer cells. METHODS: 3D multicellular structures were generated by culturing cancer cells on non-adherent surfaces; and for comparison cell monolayers were cultured on adherent culture plates. Ishikawa, RL95-2, and KLE cell lines were studied. Morphologies of 3D multicellular structures were examined. After 48 hours treatment with anticancer drugs, apoptosis, proliferation, glucose metabolism and vascular endothelial growth factor (VEGF) were analysed. Immunostaining of PCNA, Glut-1, p-Erk1/2, SOD-1 and p-Akt1/2/3 was also performed. RESULTS: Distinct 3D multicellular morphologies were formed by three different endometrial cancer cell lines. Doxorubicin induced less apoptosis in 3D multicellular structures of high grade cancer cells (RL95-2 and KLE cell lines) than in cell monolayers. Parallel alterations in Erk1/2 phosphorylation and cell proliferation might suggest they were linked and again doxorubicin had less effect on 3D multicellular structures than cell monolayers. On the other hand, there was no correlation between altered glucose metabolism and proliferation. The responses depended on cancer cell lines and were apparently not mediated by altered Glut-1 levels. The level of SOD-1 was high in 3D cell cultures. The effects on VEGF secretion were various and cancer cell line dependent. Importantly, both doxorubicin and cisplatin had selective paradoxical stimulatory effects on VEGF secretion. The microenvironment within 3D multicellular structures sustained Akt phosphorylation, consistent with it having a role in anchorage-independent pathways. CONCLUSIONS: The cancer cells responded to microenvironments in a distinctive manner. 3D multicellular structures exhibited greater resistance to the agents than 2D monolayers, and the differences between the culture formats were dependent on cancer cell lines. The effects of anticancer drugs on the intracellular mediators were not similar in 3D and 2D cultures. Therefore, using 3D cell models may have a significant impact on conclusions derived from screening drugs for endometrial carcinomas.
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Proliferation rates of cells cultured in 3D and 2D are usually different and are cell line and matrix dependent.
“The proliferation rates of cells cultured in 3D and 2D are usually different, and are cell line and matrix dependent.”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [27]
The Results (‘Effects on cell proliferation’; page unavailable) report different proliferation responses in 3D spheroids and 2D monolayers after drug treatment. The Results (‘Different subtypes of endometrial cancer generated distinct morphologies of spheroids’; page unavailable) also show that growth patterns varied among cell lines. The paper does not establish that proliferation rates are usually different across 3D and 2D cultures or that those rates depend on the matrix. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRegions of hypoxia may exist in spheroids due to lack of a transport system to remove waste from the center of the spheroid.
“Chitcholtan et al . found that regions of hypoxia may exist due to lack of a transport system to remove waste from the center of the spheroid. 27”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [27]
The Discussion (page unavailable) describes low oxygen levels in spheroid cores, supporting the possibility of hypoxic regions. It does not attribute those conditions to a lack of a transport system for removing waste; searches for waste removal and transport found no such explanation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredChitcholtan et al. observed the same pattern to a lesser degree with doxorubicin and KLE endometrial cells.
“Chitcholtan et al . observed the same pattern to a lesser degree with doxorubicin and KLE endometrial cells. 27”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [27]
A variety of cell lines showed reduced proliferation rate in 3D cultures compared to those cultured in 2D.
“A variety of cell lines showed reduced proliferation rate in 3D cultures compared to those cultured in 2D. 17,27-31”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [27]
The Results sections on cell proliferation and 3D growth (page unavailable) describe three endometrial cancer cell lines, but do not report that their proliferation rates were lower in 3D than in 2D culture. The proliferation comparison instead concerns responses to anticancer drugs; searching for an untreated 3D-versus-2D proliferation comparison did not resolve the claim. (LLM, conf=0.73)
Experimental — accuracy not yet measured
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- Authors
- Chitcholtan, K., Sykes, P. H., & Evans, J. J.
- Affiliations
- University of Otago (NZ)
- Christchurch Hospital (NZ)
- Corresponding author
- Chitcholtan, Kenny
- Venue
- Journal of Translational Medicine
- Published
- 2012-03-06
- Volume
- 10
- Issue
- 1
- Pages
- 38-38
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC3316127
- OpenAlex
- W2169461456
- Cited by
- 148
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 16 · 2021: 7 · 2020: 16 · 2019: 11 · 2018: 14 · 2017: 16 · 2016: 13 · 2015: 7 · 2014: 8 · 2013: 13 · 2012: 2
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Keywords
- endometrial cancer, doxorubicin, cisplatin, chemoresistance, multicellular spheroids, tumor microenvironment, apoptosis, glucose metabolism, VEGF secretion, Akt phosphorylation, ERK1/2 phosphorylation, SOD1, anchorage-independent growth, cancer cell lines, Ishikawa
- MeSH terms
- Antioxidants, Cell Survival, Cisplatin, Densitometry, Deoxyglucose, Doxorubicin, Female, Glucose, Humans, 4-Chloro-7-nitrobenzofurazan, Phosphorylation, Superoxide Dismutase, Tumor Cells, Cultured, Endometrial Neoplasms, Apoptosis, Spheroids, Cellular, Drug Resistance, Neoplasm, Integrin beta1, Vascular Endothelial Growth Factor A, Intracellular Space, Tissue Culture Techniques, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 1
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