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Journal of Clinical Oncology, Vol 25, No 27 (September 20), 2007: pp. 4318-4320 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.2945
Celecoxib Induces MRP-4 in Lung Cancer Cells: Therapeutic ImplicationsDepartment of Experimental Medicine and Pathology, University of Rome "La Sapienza," Rome, Italy To the Editor: In recent years, several clinical trials combining selective cyclooxygenase (COX)-2 inhibitors with standard chemotherapy have been started in lung cancer with conflicting results.1,2 While in some studies celecoxib seems to improve the efficacy of taxanes and carboplatin in early-stage lung carcinoma, a recent report from Lilenbaum et al,3 published in the Journal of Clinical Oncology, describes a reduced survival time in patients treated with a combination of celecoxib and irinotecan-docetaxel compared with patients who received chemotherapy alone. The results by Lilenbaum et al conflict strongly with other clinical studies investigating celecoxib-combined regimens in lung cancer.1,2 A skeptical interpretation of these results has been provided by Csiki and Johnson,4 who suggest that inadequate doses of celecoxib, as well as upregulation of prostaglandin E2 metabolites and consequent increase in prostaglandin E2 levels, may explain the disappointing outcome of the trial by Lilenbaum et al.
The molecular mechanisms that may account for the antitumoral efficacy of celecoxib involve targets other than COX-2. It is well known that celecoxib is able to inhibit cell cycle progression, through the inhibition of CDK-cyclin complexes as well as by increasing ceramide levels, and it also has the ability to induce apoptosis by activation of death receptors, by inhibition of Ca2+ ATPase and by affecting nuclear factor
Nevertheless, paradoxical effects of celecoxib have been recently described in lung cancer cell lines, including activation of NF In this preliminary study, we describe another paradoxical effect of celecoxib at clinically relevant concentration in lung cancer cell lines (ie, the induction of multidrug resistance-associated protein 4 [MRP-4] expression). MRP-4, which belongs to a family of ATP-binding cassette transporters, due to its ability to transport nucleoside and nucleotide analogs, as well as cyclic nucleotides, was originally involved in the resistance to antiviral drugs.7,8 More recently, it was found that the substrates transported by MRP-4 include anticancer drugs, such as cyclophosphamide, camptothecins, and topotecan.9 We evaluated MRP-4 expression at both mRNA and protein levels in human NSCLC cell lines SK-MES-1, SK-LU-1, and COLO 699N exposed to 5 and 50 µmol/L of celecoxib for 24, 48, and 72 hours. After treatment, RNAs were extracted and for each sample 1 µg of total RNA was reverse-transcribed and subjected to reverse-transcriptase polymerase chain reaction assay using specific primers for MRP-4 and GADPH as internal control. MRP-4 was weakly expressed in untreated cells, whereas a strong increase of MRP-4 expression was detected after 48 hours of celecoxib treatment (Fig 1A).
MRP-4 expression enhancement was confirmed by Western Blot by using a polyclonal anti MRP-4 antibody (Fig 1B). 8 Furthermore, cryoimmunoelectron microscopy showed clearly evident MRP-4 labeling along the inner plasma membrane, in cytoplasmic vesicles, and in secretory compartments in celecoxib-treated COLO 699N cells, while only occasional sparse cytoplasmic gold particles were observed in untreated cells (Figs 2A to 2C; arrows; data not shown). Cells were processed as described in Lotti et al.11
Taken together, all of these findings suggest that MRP-4 induction by celecoxib in lung cancer cells may account for the results obtained by Lilenbaum et al in their clinical trial.3 In fact, by inducing MRP-4 expression and its localization at the plasma membrane, celecoxib could enhance the extrusion of irinotecan from tumor cells, thus reducing the efficacy of chemotherapy and worsening prognosis of patients. From this point of view, the different effect observed by Altorki using celecoxib in association with carboplatin and taxanes in lung cancer2 may be mainly dependent on the fact that these drugs are not substrates for MRP-4. MRP-4 induction by celecoxib may also account for the increase in the average elimination clearance of irinotecan, coincident with the addition of celecoxib, as described by Argiris et al in a phase I trial.10 Further studies are now in progress in order to evaluate the mechanism of induction of MRP-4 by celecoxib in other tumor types, and to clarify whether MRP-4 may be induced by other selective COX-2 inhibitors as well. Our preliminary results, besides suggesting that the efficicacy of celecoxib in combination with standard chemotherapy may be strictly dependent on the type of drug regimen used, recommend that celecoxib-dependent induction of MRP-4 should be always taken into consideration before planning drug choice in lung cancer patients, to exclude the administration of celecoxib in combination with drugs (irinotecan, topotecan), which are substrate for MRP-4. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Krysan K, Reckamp KL, Sharma S, et al: The potential and rationale for COX-2 inhibitors in lung cancer. Anticancer Agents Med Chem 6:209-220, 2006[Medline] 2. Altorki NK, Keresztes RS, Port JL, et al: Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 21:2645-2650, 2003 3. Lilenbaum R, Socinski MA, Altorki NK, et al: Randomized phase II trial of docetaxel/irinotecan and gemcitabine/irinotecan with or without celecoxib in the second-line treatment of non-small-cell lung cancer. J Clin Oncol 24:4825-4832, 2006 4. Csiki I, Johnson DH: Did targeted therapy fail cyclooxygenase too? J Clin Oncol 24:4798-4800, 2006 5. Grosch S, Maier TJ, Schiffmann S, et al: Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 98:736-747, 2006 6. Gradilone A, Silvestri I, Scarpa S, et al: Failure of apoptosis and activation on NFkappaB by celecoxib and aspirin in lung cancer cell lines. Oncol Rep 17:823-828, 2007[Medline] 7. Borst P, de Wolf C, van de Wetering K: Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 453:661-673, 2007[CrossRef][Medline] 8. Schuetz JD, Connelly MC, Sun D, et al: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med 5:1048-1051, 1999[CrossRef][Medline] 9. Tian Q, Zhang J, Chan SY, et al: Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab 7:105-118, 2006[CrossRef][Medline] 10. Argiris A, Kut V, Luong L, et al: Phase I and pharmacokinetic study of docetaxel, irinotecan, and celecoxib in patients with advanced non-small cell lung cancer. Invest New Drugs 24:203-212, 2006[CrossRef][Medline] 11. Lotti LV, Ottini L, D'Amico C, et al: Subcellular localization of the BRCA1 gene product in mitotic cells. Genes Chromosomes Cancer 35:193-203, 2002[CrossRef][Medline] Related Reply
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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