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Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.

Oxicams (e.g. piroxicam, meloxicam) are widely used nonsteroidal anti-inflammatory drugs (NSAIDs). A large body of evidence from epidemiological and preclinical studies has shown that NSAIDs have a chemopreventive effect on different types of cancer, especially in colorectal cancer. Moreover mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. What is more, inflammation induces reactive oxygen and nitrogen species, which cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. In this study, we discuss the synthesis and the resultant newly synthesised oxicam derivatives which are potentially chemopreventive, and at the same time antioxidant. Compound 9c with highest therapeutic index in the LoVo cancer cell line was found to be the most efficient at ROS scavenging activity in the condition of oxidative stress.

The purpose of the present work was to assess the ability of five new oxicam analogues to interact with the lipid bilayers. To characterize the interaction of newly synthesized NSAIDs (non-steroidal anti-inflammatory drugs) analogues with DPPC lipid bilayers the two following techniques were applied – differential scanning calorimetry (DSC) and fluorescence spectroscopy. The results obtained by these experimental approaches show that new oxicams analogues interact with the lipid model membranes under consideration. As demonstrated both in calorimetric and spectroscopic studies, the greatest influence on the thermotropic properties of the lipid membrane and on the quenching of fluorescence of Laurdan and Prodan was exerted by a derivative named PR47 containing in its structure a two–carbon aliphatic linker with a carbonyl group, as well as bromine and trifluoromethyl substituents.

Background Incidence of cancer is still increasing. Chemotherapy is often unsuccessful; moreover, anticancer drugs cause serious side-effects. It is necessary to develop effective agents for combination therapies that would increase antitumor effects of treatment and reduce its side-effects. Materials and methods Anticancer activity of oxicam derivatives (PR17 and PR18) alone and in combination with simvastatin on doxorubicin-resistant colon cancer cells was studied. Apoptosis was investigated via caspase-3 activation assay as well as via western blot analysis of expression of apoptotic components, B-cell lymphoma 2 protein (BCL2) and BCL2-associated X protein (BAX). Expression and activity of cyclo-oxygenase-2 (COX2) was also assessed. Results Oxicam derivatives induced apoptosis through a caspase-3-dependent pathway, up-regulated BAX expression, and down-regulated BCL2 expression. Additionally, oxicam derivatives reduced expression and activity of COX2. Effect of oxicam derivatives on these processes was strongly potentiated by simvastatin. Conclusion Oxicam derivatives at low concentrations effectively inhibit growth of cancer cells after co-administration with simvastatin.

Novel arylpiperazine-1,2-benzothiazine derivatives have been designed and synthesized as potential anti-inflammatory agents. Their structure and properties have been studied using spectroscopic techniques (1H NMR, 13C NMR, FT-IR), MS, elemental analyses, and single-crystal X-ray diffraction (SCXRD, for compound 7b). This study aimed to evaluate the inhibitory activity of new derivatives against both cyclooxygenase isoforms COX-1 and COX-2 due to the similarity of new compounds to oxicams drugs from the NSAIDs group. All new compounds were divided into two series – A and B – with a different linker between thiazine and piperazines nitrogens. Series A included the three-carbon aliphatic linker and series B – two-carbon with a carbonyl group. According to in vitro and molecular docking studies all new compounds exhibited cyclooxygenase inhibitory activity. The series of A compounds included COX-1 inhibitors only. In contrast, the B series showed inhibition of both COX-1 and COX-2, which suggested the importance of the acetoxy linker for COX-2 inhibition. Moreover, the most selective compound 7b, towards COX-2, was non-toxic for the normal human cell line (in concentration of 10 µM) comparable to reference drug meloxicam. Additionally, investigation of influence on model membranes confirmed the ability of the compound 7b to penetrate lipid bilayers which seemed to be important to the influence with membrane protein-cyclooxygenase.

Simple Summary Nitric oxide and arginine metabolism in colorectal cancer (CRC) holds potential for therapeutic intervention. We hypothesized that it can be modulated by oxicams, a class of non-steroidal anti-inflammatory drugs with documented chemopreventive and antineoplastic activity. The aim of this study was to determine the transcriptional patterns of pathway enzymes in CRC and evaluate the impact of classic and new oxicam analogues. Arginine metabolic pathways were altered not only in tumors but also in non-transformed mucosa from tumor vicinity, contributing to the phenomenon of tumor molecular margin. Classic oxicams, piroxicam and meloxicam, had negligible impact but their new analogues downregulated expression of dimethylarginine dimethylaminohydrolases and protein methyltransferases and upregulated asymmetric dimethylarginine. Those beneficial effects were accompanied by upregulation of arginase-2 and the potentially disadvantageous accumulation of arginine and symmetric dimethylarginine. Our findings provide novel insight into metabolic reprogramming in CRC and demonstrate that oxicam analogues are worth further consideration as novel anticancer agents. Abstract L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.