Oxicams belong to a class of non-steroidal anti-inflammatory drugs (NSAIDs). Antitumor potential of commonly used non-steroidal anti-inflammatory drugs is currently often reported in literature. NSAIDs are inhibitors of cyclooxygenase-2 (COX-2), the enzyme expressed in the most of solid tumors. COX-2 is also involved in multidrug resistance - the expression of COX-2 is well correlated with overexpression of multidrug resistance transporter MDR1/P-gp.It has been suggested that COX-2 inhibitors can sensitize cancer cells to anticancer drugs by inhibition of MDR transporters, such as P-gp, MRP1 and BCRP.

The aim of our studies was to obtain two new piroxicam derivatives: PR17 and PR18 possessing anticancer and/or multidrug resistance reversing activity. Compounds should inhibit both COX-2 enzyme and MDR transporters’ activity. Human colorectal adenocarcinoma cell line LoVo and its doxorubicin-resistant subline Lovo/Dx were chosen to study multidrug reversal activity of newly synthetized oxicams. Expression of MDR transporters in LoVo and LoVo/Dx human colon adenocarcinoma cell lines was studied. The effect of new oxicams on expression of mRNA of P-gp, MRP1 and BCRP was determined by RT-PCR. The effect of the compounds on protein expression was checked by Western-Blot. The influence of oxicams on transport activity of P-gp was studied by flow cytometry using Rhodamine 123 as fluorescent substrate for P-gp. Compounds cytotoxicity and cytotoxicity of doxorubicin in the presence of oxicams were determined by SRB assay using microplate reader.

Molecular modeling (geometry optimization in vacuum, ab initio HF) was applied to describe electronic and structural parameters andhydrophobicity of the oxicam derivatives, andthese features were compared with ability of the compoundsto reverse MDR phenotype and with their cytotoxicity in adenocarcinoma cells.

Two new synthesized compounds from oxicam group of drugs, PR17 and PR18 are able to modulate MDR phenotype in human adenocarcinoma cells. Both compounds, PR17 and PR18 restore accumulation of fluorescent P-gp substrate in resistant adenocarcinoma cells and they reduce Rh123 efflux much more efficiently than verapamil, well known P-gp inhibitor.

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