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Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response
L C Young1, B G Campling, T Voskoglou-Nomikos
1Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Abstract:
Recently, cDNAs have been identified that encode four human proteins (MRP2-5) with structural similarity to the multidrug resistance protein (MRP). Preliminary studies have shown that levels of mRNAs encoding MRP2, MRP3, and MRP5, are increased in some drug-selected cell lines, but the correlation of MRP2-5 mRNA levels with drug resistance has not been examined. Using a collection of small cell lung cancer (SCLC) and non-SCLC patient samples and unselected cell lines established from patients at various stages of treatment, we examined the expression of MRP2, MRP3, MRP4, and MRP5, as well as MDR1 and MRP, by PCR. The levels of individual mRNAs were correlated with the sensitivity of these cell lines to doxorubicin (DOX), vincristine, VP-16, and cis-diamminedichloroplatinum(II), as determined by a modified MTT assay. Using both SCLC and non-SCLC cell lines, we confirmed the previously observed correlation of MRP mRNA levels with resistance to DOX (B. G. Campling et al., Clin. Cancer Res., 3:115-122, 1997) and found a strong correlation of MRP3 mRNA levels with resistance of the cell lines to DOX. In addition, the mRNA levels of both MRP and MRP3 correlated with resistance of the cell lines to vincristine, VP-16, and cis-diamminedichloroplatinum(II). These findings are consistent with the suggestion that MRP3, like MRP, may contribute to the drug resistance phenotype of lung cancer cells.
Insights
Multidrug resistance-associated protein 3 (MRP3) mRNA levels correlate with resistance to common chemotherapy drugs in lung cancer. This suggests MRP3 contributes to multidrug resistance in lung cancer cells.
Area of Science:
- Molecular biology
- Cancer research
- Pharmacology
Background:
- Four human proteins (MRP2-5) with structural similarity to multidrug resistance-associated protein (MRP) have been identified.
- Previous studies indicated increased mRNA levels of MRP2, MRP3, and MRP5 in drug-selected cell lines, but direct correlation with drug resistance was unexamined.
Purpose of the Study:
- To investigate the correlation between mRNA expression levels of MRP2, MRP3, MRP4, and MRP5 and drug resistance in lung cancer.
- To determine if MRP3 contributes to the multidrug resistance phenotype in lung cancer cells.
Main Methods:
- Quantitative PCR (PCR) was used to examine mRNA expression of MRP2, MRP3, MRP4, MRP5, MDR1, and MRP in small cell lung cancer (SCLC) and non-SCLC cell lines.
- Cell line sensitivity to doxorubicin (DOX), vincristine, VP-16, and cis-diamminedichloroplatinum(II) was assessed using a modified MTT assay.
Main Results:
- A strong correlation was found between MRP3 mRNA levels and resistance to doxorubicin (DOX) in both SCLC and non-SCLC cell lines.
- MRP and MRP3 mRNA levels correlated with resistance to vincristine, VP-16, and cis-diamminedichloroplatinum(II).
- Previously observed correlation of MRP mRNA levels with DOX resistance was confirmed.
Conclusions:
- MRP3 mRNA levels are strongly associated with resistance to DOX in lung cancer.
- Both MRP and MRP3 mRNA expression correlate with resistance to a range of chemotherapy drugs, including vincristine, VP-16, and platinum compounds.
- These findings support the role of MRP3 in contributing to the multidrug resistance phenotype in lung cancer cells.