Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin

• Published in: British journal of cancer Vol. 76; no. 1; pp. 67 - 76
• Main Authors: DOLFINI, E, DASDIA, T, ARANCIA, G, MOLINARI, A, CALCABRINI, A, SCHEPER, R. J, FLENS, M. J, GARIBOLDI, M. B, MONTI, E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 1997
• Subjects: Adenocarcinoma - metabolism; Antineoplastic agents; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Clone Cells; Colonic Neoplasms - metabolism; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Flow Cytometry; General aspects; Glutathione - metabolism; Medical sciences; Multidrug Resistance-Associated Proteins; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Protein Kinase C - metabolism; Time Factors; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles; Adenocarcinoma; Antineoplastic agent; Human; Molecular form; Protein kinase C; Enzyme; Transferases; P Glycoprotein; Malignant tumor; Doxorubicin; Antibiotic; Multiple resistance; Established cell line; Anthracyclins; Colon; Negative therapeutic reaction; Glutathione
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1997.338

Intrinsic low-level resistance to anti-cancer drugs is a major problem in the treatment of gastrointestinal malignancies. To address the problem presented by intrinsically resistant tumours, we have isolated two monoclonal lines from LoVo human colon adenocarcinoma cells: LoVo/C7, which is intrinsically resistant to doxorubicin (DOX); and LoVo/C5, which shows the same resistance index for DOX as the mixed parental cell population. For comparison, we have included in the study a LoVo-resistant line selected by continuous exposure to DOX and expressing a typical multidrug resistant (MDR) phenotype. In these cell lines we have studied the expression and/or activity of a number of proteins, including P-glycoprotein 170 (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione (GSH)-dependent enzymes and protein kinase C (PKC) isoforms, which have been implicated in anti-cancer drug resistance. Intracellular DOX distribution has been assessed by confocal microscopy. The results of the present study indicate that resistance in LoVo/C7 cells cannot be attributed to alterations in P-gp, LRP or GSH/GSH-dependent enzyme levels. Increased expression of MRP, accompanied by alterations in the subcellular distribution of DOX, has been observed in LoVo/C7 cells; changes in PKC isoform pattern have been detected in both intrinsically and pharmacologically resistant cells.