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Updated: Mar 23, 2026
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Development and characterization of an in vitro model of colorectal adenocarcinoma with MDR phenotype
Lorenzo Cinci1, Cristina Luceri1, Elisabetta Bigagli1
1Departments of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
Abstract:
The major cause of failure in cancer chemotherapy is the development of multidrug resistance (MDR), and the characterization of biological factors involved in this response to therapy is particularly needed. A doxorubicin-resistant HCT-8/R clone was selected from sensitive parental cells and characterized analyzing several parameters (cell cycle phase distribution, apoptotic activity, expression, distribution and functionality of the P-gp efflux pump, the response to other chemotherapy agents, its ultrastructural features, invasiveness, and transcriptomic profile). HCT-8/R cells showed a peculiar S phase distribution, characterized by a single pulse of proliferation, resistance to drug-mediated apoptosis, increased expression and functionality of P-gp and overexpression of stem cell markers (CD44 and aldehyde dehydrogenase 1A2). At the ultrastructural level, HCT-8/R presented a greater cell volume and several intracytoplasmic vesicles respect to HCT-8. Moreover, the resistant clone was characterized by cross resistance to other cytotoxic drugs and a greater capacity for migration and invasion, compared to parental cells. Our data reinforce the concept that the MDR phenotype in HCT-8/R cells is multifactorial and involves multiple mechanisms, representing an interesting tool to understand the biological basis of MDR and to test strategies that overcome resistance to chemotherapy.
Insights
Multidrug resistance (MDR) in cancer chemotherapy is multifactorial. Characterizing resistant cells reveals mechanisms like P-gp efflux pump activity and stem cell marker overexpression, aiding in overcoming treatment failure.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Multidrug resistance (MDR) is a primary cause of cancer chemotherapy failure.
- Understanding the biological factors driving MDR is crucial for developing effective treatments.
Purpose of the Study:
- To characterize a doxorubicin-resistant HCT-8/R cell clone to elucidate the mechanisms of MDR.
- To analyze various cellular and molecular parameters of the resistant clone compared to its sensitive parental cells.
Main Methods:
- Selection and characterization of a doxorubicin-resistant HCT-8/R cell clone.
- Analysis of cell cycle distribution, apoptosis, P-glycoprotein (P-gp) expression and function, stem cell marker expression, ultrastructural features, invasiveness, and transcriptomic profile.
Main Results:
- HCT-8/R cells exhibited a unique S phase distribution, resistance to apoptosis, increased P-gp expression and function, and overexpression of CD44 and aldehyde dehydrogenase 1A2 stem cell markers.
- Ultrastructural analysis revealed larger cell volume and intracytoplasmic vesicles in HCT-8/R cells.
- The resistant clone demonstrated cross-resistance to other cytotoxic agents and enhanced migration and invasion capabilities.
Conclusions:
- The MDR phenotype in HCT-8/R cells is multifactorial, involving multiple interconnected mechanisms.
- This resistant clone serves as a valuable model for investigating the biological basis of MDR and testing novel therapeutic strategies to overcome chemotherapy resistance.
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