title: Heterogeneity in cancer cells: variation in drug response in different primary and secondary colorectal cancer cell lines in vitro.
abstract: Tumor heterogeneity may give rise to differential responses to chemotherapy drugs. Therefore, unraveling tumor heterogeneity has an implication for biomarker discovery and cancer therapeutics. To test this phenomenon, we investigated the differential responses of three secondary colorectal cancer cell lines of different origins (HCT116, HT29, and SW620 cells) and four novel primary cell lines obtained from different colorectal cancer patients to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) and explored the differences in gene expression among the primary cell lines in response to exposure to cytotoxic drugs. Cells were exposed to different doses of 5-FU and L-OHP separately or in combinations of equitoxic drug or equimolar drug ratios (median effect of Chou-Talalay principle). Cell viability was assessed using MTT assay and the respective IC50values were determined. Changes in gene expression in primary cell lines after exposure to the same drug doses were compared using real-time PCR array. The sensitivities (IC50) of different cell lines, both secondary and primary, to 5-FU and L-OHP were significantly different, whether in monotherapy or combined treatment. Primary cell lines needed higher doses to reach IC50. There were variations in gene expression among the primary cell lines of different chemosensitivities to the challenge of the same combined dose of 5-FU and L-OHP. The results confirm the heterogeneous nature of colorectal cancer cells from different patient tumors. Studies using primary cancer cells established from patient's tumors rather than secondary cell lines will more closely reflect the actual character of the disease.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. melanie_arul@yahoo.com.sg.
authors.forename: Melanie
authors.identifier: http://orcid.org/0000-0002-3666-762X
authors.initials: M
authors.lastname: Arul
authors.affiliation: Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: April Camilla
authors.initials: AC
authors.lastname: Roslani
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. cheahsh@ummc.edu.my.
authors.forename: Swee Hung
authors.initials: SH
authors.lastname: Cheah
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D054316:Biomarkers, Pharmacological; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage; D018740:Genetic Heterogeneity / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D054316:Biomarkers, Pharmacological; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil
keywords: Chou-Talalay; Colorectal cancer; Drug combination; Fluorouracil; Oxaliplatin