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Effect of New Oxicam Derivatives on Efflux Pumps Overexpressed in Resistant a Human Colorectal Adenocarcinoma Cell Line

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Effect of New Oxicam Derivatives on Efflux Pumps Overexpressed in Resistant a Human Colorectal Adenocarcinoma Cell Line ANTICANCER RESEARCH 35: 2835-2840 (2015) Effect of New Oxicam Derivatives on Efflux Pumps Overexpressed in Resistant a Human Colorectal Adenocarcinoma Cell Line KAMILA ŚRODA-POMIANEK1, OLGA WESOŁOWSKA1, BERENIKA SZCZĘŚNIAK-SIĘGA2, BARTOSZ PUŁA3, PIOTR DZIĘGIEL3, JADWIGA MANIEWSKA2, WIESŁAW MALINKA2, ANNA PALKO-ŁABUZ1 and KRYSTYNA MICHALAK1 Departments of 1Biophysics, 2Chemistry of Drugs, and 3Histology and Embryology, Wroclaw Medical University, Wroclaw, Poland Abstract. Background: Oxicams are non-steroidal anti- mechanisms. The most important among them are altered drug inflammatory drugs (NSAIDs). Antitumor potential of activation or degradation (1), as well as altered membrane NSAIDs has often been reported in literature. We studied transport either by decreased drug uptake or by increased drug antitumor activity of newly synthesized oxicam derivatives efflux (2). The development of resistance to multiple (PR17 and PR18) against doxorubicin-sensitive and resistant chemotherapeutic agents by cancer cells often results from human colorectal adenocarcinoma cells (LoVo and elevated expression of ATP-binding cassette (ABC) drug LoVo/Dx). Materials and Methods: The cytotoxicity of transporters in the cell membrane and constitutes a major oxicam derivatives alone and in combination with factor responsible for the failure of chemotherapy. Many ABC doxorubicin was assessed. Inhibition of P-glycoprotein proteins play a key role in pharmacokinetics affecting entry (ABCB1) transport activity was monitored by flow cytometry. and extrusion of drugs into and out of cells. In particular, Expression of ABCB1 gene was analyzed by semi- overexpression of P-glycoprotein (ABCB1) plays a significant quantitative reverse transcription PCR, while ABCB1 protein role in chemoresistance. This protein is believed to act as an expression was assessed by western blotting. Results: energy-dependent efflux-pump for a variety of structurally- Oxicam derivative PR18 was more cytotoxic to cancer cells diverse chemotherapeutic agents, thereby decreasing their than PR17. PR18 was observed to sensitize LoVo/Dx cells to intracellular accumulation (3). Consequently, cancer cells can doxorubicin and was identified as an effective multidrug evade the cytotoxic effect of anticancer drugs. New data on resistance modulator. Additionally, ABCB1 expression was the antitumor potential of commonly used non-oncological reduced in the presence of PR18. Conclusion: PR18 was drugs, such as non-steroidal anti-inflammatory drugs identified as an effective modulator in LoVo/Dx resistant (NSAIDs) have recently appeared in literature (4, 5), and the human colorectal adenocarcinoma cells which overexpressed challenge is to obtain new, more active compounds possessing ABCB1 efflux pump. anticancer or multidrug resistance-reversing activity. Many studies have indicated that NSAIDs may reduce the risk of The development of safe and effective cancer therapy is a cancer incidence, including of breast, colon, lung, and stomach continuing to be a scientific aim. Despite the existence of new cancer (5). Piroxicam is a NSAID of the oxicam class used as technologies, the fight against cancer is too often ineffective. an analgesic and to relieve the symptoms of rheumatoid and The major risk in cancer chemotherapy is that the cancer may osteoarthritis, primary dysmenorrhea, and postoperative pain. develop resistance to the used drug. Cancer cells exposed to NSAIDs are inhibitors of the cyclooxygenases (COXs) a toxic compounds can develop resistance by a number of family of enzymes which catalyze the rate-limiting step of prostaglandin biosynthesis. COX2 was described as modulating cell proliferation and apoptosis, mainly in solid tumors, that is, colorectal, breast, and prostate cancer, and, Correspondence to: Kamila Środa-Pomianek, Department of more recently, in hematological malignancies (6-8). Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, Immunohistochemical analyses of human breast tumor 50-368 Wrocław, Poland. Tel: +48 717841406, Fax: +48 specimens revealed a strong correlation between expression 717840088, e-mail: [email protected] of COX2 and P-glycoprotein (9). Surowiak et al. (9) Key Words: Multidrug resistance (MDR), P-glycoprotein, non-steroidal mentioned that COX2 might be the factor responsible for the anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX2). regulation of expression not only of P-gp but also of two 0250-7005/2015 $2.00+.40 2835 ANTICANCER RESEARCH 35: 2835-2840 (2015) Table I. The sequences of primers and sizes of amplification products. properties with their ability to affect phospholipid bilayers (18). The calorimetric measurements obtained by Maniewska Gene Sequence of primers Amplification et al. revealed that PR17 and PR18 interact with the product (bp) phosphatidylcholine bilayer and change the lipid phase (18). ABCB1 Forward: 5’-AAGCTTAGTACC Additionally, the presence of a carbonyl group increased the AAAGAGGCTCTG-3’ ability of PR18 to interact with model membranes. Reverse:5’-GGCTAGAAACAATAGTG The aim of the present study was to determine the AAAACAA-3’ 243 anticancer properties of the two, newly-synthesized oxicam GUS Forward: 5’-CTGCCGCAGTTCTT CAACAACG-3’ analogs, PR17 and PR18 (Figure 1) against doxorubicin- Reverse: 5’-CGTCGGTGACTGTT sensitive and -resistant human colon adenocarcinoma cell CAGTCATG-3’ 558 lines, LoVo and Lovo/Dx. Expression of MDR-related transporters in both cell lines was previously characterized by reverse transcription-polymerase chain reaction (RT-PCR) and immunochemical methods and elevated expression of P- other ABC transporters: the multidrug resistance-associated glycoprotein was accepted to be responsible for doxorubicin- protein 1 (MRP1, ABCC1) and the breast cancer resistance resistance in LoVo/Dx cells (19). The effect of the studied protein (BCRP, ABCG2). It has been suggested that COX compounds on transport function of P-glycoprotein as well inhibitors can sensitize cancer to chemotherapeutic drugs by as on P-glycoprotein expression was also investigated. inhibiting P-glycoprotein, MRP1 and BCRP, thus enhancing the cytotoxicity of anticancer drugs (10, 11). These effects of Materials and Methods NSAIDs have been demonstrated in several different malignancies (12, 13). Moreover, cancer cells with the Oxicam derivatives. PR17 [(4-chlorophenyl)-{2-[3-[4-(2-fluorophenyl) multidrug resistance (MDR) phenotype often display other piperazin-1-yl]propyl]-4-hydroxy-1,1-dioxo-1,2-benzothiazin-3- properties, such as genomic instability, loss of checkpoint yl}methanone] and PR18 (2-[3-(4-chlorobenzoyl)-4-hydroxy-1,1- control or resistance to apoptosis, which also hamper dioxo-1,2-benzothiazin-2-yl]-1-[4-(fluorophenyl)piperazin-1- successful chemotherapy (14). Pre-clinical and clinical studies yl]ethanone) were synthesized as previously described (18) (see Figure suggest that COX2 inhibitors are highly promising agents not 1). In PR18 1,2-benzothiazine ring is connected to 2-fluoro- only for the treatment of pain and inflammation, but also for phenylpiperazine by a methylene carbonyl linker, while PR17 possesses a propyl linker, which is one carbon atom longer. The the prevention of cancer (15). Treatment with COX2-specific compounds were dissolved in dimethylsulfoxide (DMSO). inhibitors results in a wide range of cellular effects, including induction of apoptosis, reduction of cell proliferation and Cell culture. Sensitive (LoVo) and doxorubicin-resistant human colon enhanced cytotoxicity of anticancer drugs (16, 17). adenocarcinoma cell line (LoVo/Dx) were obtained from the Institute It is well-known that pharmacological actions of drugs of Immunology and Experimental Therapy (Polish Academy of may be a consequence of their direct interaction with Sciences, Wroclaw, Poland). Both cell lines were grown in proteins (e.g. transporters) or their influence on biophysical Dulbecco’s medium supplemented with 10% fetal bovine serum, L- glutamine and antibiotics. LoVo/Dx cells were grown in the presence properties of biological membranes which, in turn, may of doxorubicin (Sigma-Aldrich, Poznan, Poland) (100 ng/ml). Cells affect protein conformation. The therapeutic action of were grown at 37˚C in a humidified atmosphere containing 5% CO2. NSAIDs may also be the result of the indirect inhibition of In log-phase of growth, they were removed from the flask surface COX due to their disruptive effect on membrane properties. with non-enzymatic cell dissociation solution (Sigma-Aldrich, The traditional methods of searching for the relationship Poznan, Poland) . The density of cells in suspension was determined between chemical structure and pharmacological activity of a using Burker hemocytometer and was generally about 106/ml. drug are now supported by the use of molecular modeling Sulphorhodamine B (SRB) assay. Cell viability was determined using techniques. Structure–activity relationship studies open up the SRB assay (20) with minor modifications. Sulphorhodamine is a possibility of better understanding of the properties of protein-binding dye that binds to the basic amino acids of cellular biological systems based on the molecular structure of the macromolecules and it is used in the end-point determination of cell interacting molecules. Quantitative methods for study of the growth. Cells (4×104 cells per well) were seeded into 96-well plates structure-activity relationship (QSAR) allow for electronic, in 75 μl of medium and were allowed to attach for 60 min at 37˚C. structural and topological parameters
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