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Association between expression of the MRP3 gene and exposure to platinum drugs in lung cancer
1Second Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan. oguri@mcai.med.hiroshima-u.ac.jp
Abstract:
To investigate the roles played by the multidrug resistance-associated protein (MRP1) homologues MRP3 and MRP4 in resistance to platinum drugs, we examined steady-state levels of mRNA for both MRP3 and MRP4 in normal lung and lung cancer specimens as well as peripheral mononuclear cells (PMN) after platinum drug exposure. MRP3 and MRP4 gene expression levels were monitored in the PMN of 10 previously untreated lung cancer patients within 24 hr after carboplatin (CBDCA) administration. Expression levels for both genes were also examined in 80 autopsy samples (40 primary tumors and 40 corresponding normal lung tissues) from 40 patients with lung cancer. MRP3 and MRP4 gene expression levels were assessed by quantitative reverse transcription-polymerase chain reaction. MRP3 expression levels in the PMN rose rapidly within 24 hr after administration of CBDCA, whereas MRP4 expression levels remained the same. Furthermore, MRP3 expression levels in normal lung and tumor tissues from autopsy samples that had been exposed to platinum drugs while the patients were alive were significantly higher than those in unexposed tissues, but again MRP4 expression levels remained the same. These results suggest that platinum drugs and/or the physiological stress response to xenobiotics induce expression of the MRP3 gene.
Insights
Platinum drugs increase multidrug resistance-associated protein 3 (MRP3) gene expression in lung cancer patients, but not MRP4. This suggests MRP3 plays a role in platinum drug response and resistance.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- Multidrug resistance-associated proteins (MRPs) are key in drug efflux.
- MRP1 homologues, MRP3 and MRP4, roles in platinum drug resistance are unclear.
- Understanding MRP roles is crucial for cancer chemotherapy.
Purpose of the Study:
- Investigate MRP3 and MRP4 roles in platinum drug resistance.
- Examine MRP3 and MRP4 gene expression in lung cancer patients and tissues.
- Determine if platinum drugs affect MRP3 and MRP4 expression.
Main Methods:
- Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) used for gene expression analysis.
- Examined MRP3 and MRP4 mRNA levels in peripheral mononuclear cells (PMNs) of lung cancer patients post-carboplatin (CBDCA).
- Assessed gene expression in autopsy lung tissues (normal and tumor) from patients with and without prior platinum drug exposure.
Main Results:
- MRP3 mRNA levels in PMNs significantly increased within 24 hours after CBDCA administration.
- MRP4 mRNA levels in PMNs remained unchanged post-CBDCA.
- MRP3 expression was significantly higher in autopsy lung tissues exposed to platinum drugs compared to unexposed tissues.
- MRP4 expression showed no significant difference between exposed and unexposed tissues.
Conclusions:
- Platinum drugs, such as carboplatin, induce MRP3 gene expression.
- The physiological stress response to xenobiotics may also induce MRP3 expression.
- MRP3, but not MRP4, appears to be involved in the response to platinum drugs in lung cancer.
