MRP gene overexpression in a human doxorubicin-resistant SCLC cell line: Alterations in cellular pharmacokinetics and in pattern of cross-resistance

✍ Scribed by Monica Binaschi; Rosanna Supino; Romolo A. Gambetta; Giuseppe Giaccone; Ennio Prosperi; Giovanni Capranico; Ignazio Catalog; Franco Zunino

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: French
• Weight: 697 KB
• Volume: 62
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910620116

✦ Synopsis

Abstract

The development of non‐P‐glycoprotein‐mediated multidrug resistance is a frequent event among lung‐cancer cell lines. In an attempt to understand the underlying mechanisms of this phenotype, we have selected a multi‐drug‐resistant subline (POGB/DX) in vitro for doxorubicin resistance. The original cell line (POGB) was established in vitro from a non‐treated patient with a small‐cell lung cancer. POGB/DX cells were crossresistant to other drugs, associated with MDR phenotype. In contrast, they were not resistant to taxol, camptothecin or melphalan, but were instead hypersensitive to 5‐fluorouracil. Although expression of the mdr‐l gene was not detected in POGB/DX cells, cellular pharmacokinetics showed a reduced drug accumulation and altered intracellular localization in the POGB/DX cell line. This defect in drug accumulation was associated with overexpression and amplification of the MRP gene. Interestingly, verapamil, a known modulator of P‐glycoprotein function, was able to reverse drug resistance and to increase drug accumulation. In Northern‐blot analysis no differences in expression of topoisomerase I and II (α and β), DNA polymerase β, or HSP70 and HSP60 genes were observed between POGB and POGB/DX. Coupled to lack of changes in expression of known resistance factors, over expression of MRP and modulation by verapamil strongly support a role for this gene product in the development of drug resistance in this SCLC cell system. This study provides evidence that (a) altered cellular pharmacokinetics is related to MRP expression; (b) MRP‐mediated phenotype is characterized by a specific pattern of cross‐resistance, which does not involve taxol; and (c) verapamil may be effective in modulating the function of the MRP gene product. © 1995 Wiley‐Liss Inc.