Multidrug resistance in small cell lung cancer: Expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease
Introduction
Drug resistance is one of the most important causes of unsuccessful lung cancer chemotherapy. Some tumours are initially resistant and never respond to cytostatic drug treatment; whereas others become resistant after a good initial response [1]. Multidrug resistance is cross-resistance to some structurally and functionally unrelated naturally derived drugs, such as epipodophyllotoxins, vinka alcaloids, antracyclines, taxanes, colchicines and others, and is mostly caused by overexpression of P-gp and MRP [2], [3].
In small cell lung cancer (SCLC), resistance is usually associated with the emergence of drug-resistant cell clones during chemotherapy [4]. Studies of cell culture systems have established that tumour cells exposed to only a single drug expressed cross-resistance to a broad range of structurally and functionally dissimilar drugs. While various mechanisms may contribute to chemotherapy resistance, the primary ones are the so-called “pump” and “non-pump” forms of resistance [5], [6]. The basic mechanism of non-pump resistance is activation of cellular antiapoptotic defence. Pump resistance or transport-mediated resistance is due to the decreased concentration of the active drug in target cells because of decreased drug uptake or increased drug efflux across tumour cell membranes, or to increased drug efflux through cytoplasmic vesicles. Certain proteins are able to transport toxic materials and drugs across cellular membranes, against a concentration gradient, decreasing their intracellular concentration [7]. A large subclass of these proteins is ATP-binding cassette (ABC) proteins, which are expressed in both normal and malignant cells. The main ABC transporters are P-gp and MRP1. The 170 kDa MDR1 P glycoprotein (P-gp) was the first human ABC transporter to be identified, and therefore most of our knowledge regarding these transporters is based on studies of P-gp. The 190 kDa multidrug resistance protein (MRP1) is probably involved in an antioxidant defence mechanism. Most drug-resistant lung cancers overexpress both P-glycoprotein and MRP1 [1], [8], [9].
While the lung resistance protein (LRP) is not an ABC transporter, it is a major vault protein, and is found in the cytoplasm and nuclear membrane. LRP is responsible for the uptake of drugs in cytoplasmic vesicles that are then probably extruded from the cell by exocytosis. Some investigators have reported that overexpression of LRP correlates with resistance to cisplatin [10].
The aim of our study was to investigate the expression levels of P-gp, MRP1 and LRP at diagnosis in chemo-naive patients and to determine if any correlation exists between expression levels and the overall response to chemotherapy. We also investigated the levels of those proteins in patients with relapsed disease.
Section snippets
Patient selection
We initiated a prospective study after it was approved by the state ethical committee and once patients had given their informed consent. The study focused on patients with ECOG performance status 0 or 1 who had clearly positive and morphologically evident SCLC in samples obtained from mediastinal lymph nodes and who had no prior chemotherapy or radiotherapy. We excluded all patients with SCLC whose mediastinal lymph nodes were not involved with SCLC tumour cells or from whom samples from
Results
A total of 17 patients (7 women, 10 men; median age 68 years [range: 40–72]) were included in the present analysis. The results of P-gp (JSB-1), MRP1 and LRP expression in metastatic SCLC cells in chemo-naive patients in comparison to chemotherapy response according to RECIST criteria are summarized in Fig. 3, Fig. 4. The response rate to chemotherapy showed progressive disease in two patients, stable disease in three patients, partial response in four patients and complete response in nine
Discussion
The aim of the present study was to investigate P-gp, MRP1 and LRP expression in SCLC cells. To our knowledge, this is the first report comparing the levels of transporter expression in metastatic SCLC cells with chemotherapy response and their levels in relapsed disease.
Our results clearly indicate that chemotherapy response is strongly associated with the level of P-gp expression in all 17 chemo-naive SCLC patients. A low level of P-gp expression was associated with a good chemotherapy
Conclusion
Our results confirm that the expression level of P-gp strongly correlates with the degree of response to chemotherapy and that the levels of P-gp, MRP1 and LRP usually increase in relapsed disease. Advances in diagnostic techniques and the possibility of accurate selection of patients with tumours that overexpress the aforementioned transporters should result in more successful treatment of SCLC with drugs that are not dependent on the ABC transport system, with new targeted therapies, or with
Acknowledgement
This study was supported by Slovenian Ministry of Science (grant no. J3-6126) and by the Cholewa Foundation.
References (28)
- et al.
Multidrug resistance in non-small cell lung cancer
Ann Oncol
(1999) - et al.
Intraoperative detection of lymph node micrometastasis with flow cytometry in non-small cell lung cancer
J Thorac Cardiovasc Surg
(2005) - et al.
Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukaemia: a Southwest Oncology Group study
Blood
(1999) - et al.
Multidrug resistance genes (MRP) and MDR1 expression in small cell lung cancer xenografts: relationship with response to chemotherapy
Cancer Lett
(1998) - et al.
Expression of the human major vault protein LRP in human lung cancer samples and normal lung tissues
Ann Oncol
(1996) - et al.
The biochemistry of P-glycoprotein-mediated multidrug resistance
Ann Rev Biochem
(1989) - et al.
Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs
Cancer Res
(1994) - et al.
Chemotherapy of small cell lung cancer
- et al.
Simultaneous modulation of multidrug resistance and antiapoptotic cellular defence by MDR1 and BCL2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin
Pharm Res
(2003) - et al.
Molecular targeting of drug delivery systems to cancer
Curr Drug Targets
(2004)
The movement of molecules across cell membranes
A case of pulmonary adenocarcinoma with overexpression of multidrug resistance-associated protein and p53 aberration
Anticancer Res
Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression
Lung
Expression of the major vault protein LRP in human non-small cell lung cancer cells: activation by short-term exposure to antineoplastic drugs
Int J Caner
Cited by (101)
A comprehensive review on acridone based derivatives as future anti-cancer agents and their structure activity relationships
2022, European Journal of Medicinal ChemistryPathogenesis and therapeutic strategy in platinum resistance lung cancer
2021, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Multidrug resistance transporters are also associated with platinum resistance. For example, ABCB1 as an ATP-binding cassette transporter belonging to P-glycoproteins (P-gp) or MRP1, promotes a variety of anticancer drugs efflux [24]. Rosmarinic acid inhibits NSCLC cell growth and increases the sensitivity of cell lines resistant to platinum by inhibiting the expression of ABCB1 [25].
Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+ leukemia cells
2023, Cell Death and DiseaseZ-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer
2023, International Journal of Molecular Sciences