title: Development and characterization of an in vitro model of colorectal adenocarcinoma with MDR phenotype.
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.
authors.affiliation: Departments of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cinci
authors.affiliation: Departments of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Luceri
authors.affiliation: Departments of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bigagli
authors.affiliation: Diagnostic Genetics Unit, Azienda Ospedaliero Universitaria "Careggi", Largo Brambilla 5, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Carboni
authors.affiliation: Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Paccosi
authors.affiliation: Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
authors.forename: Astrid
authors.initials: A
authors.lastname: Parenti
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Largo Brambilla 5, Florence, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Guasti
authors.affiliation: Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale G. Pieraccini 6, Florence, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Coronnello
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D055028:Comparative Genomic Hybridization; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015415:Biomarkers; D004317:Doxorubicin
keywords: Colorectal cancer; multi drug resistance; trascriptomics