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L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

Małgorzata Krzystek-Korpacka, Berenika Szczęśniak-Sięga, Izabela Szczuka, Paulina Fortuna, Marek Zawadzki, Agnieszka Kubiak, Magdalena Mierzchała-Pasierb, Mariusz G. Fleszar, Łukasz Lewandowski, Paweł Serek, Natalia Jamrozik, Katarzyna Neubauer (+4 others)
2020 Cancers  

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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
more » ... ue 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.
doi:10.3390/cancers12092594 pmid:32932854 pmcid:PMC7564351 fatcat:kzns72gnsfe6jfxpdqim3yl5iq
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Małgorzata Krzystek-Korpacka, Berenika Szczęśniak-Sięga, Izabela Szczuka, Paulina Fortuna, Marek Zawadzki, Agnieszka Kubiak, Magdalena Mierzchała-Pasierb, Mariusz G. Fleszar, Łukasz Lewandowski, Paweł Serek, Natalia Jamrozik, Katarzyna Neubauer, Jerzy Wiśniewski, Radosław Kempiński, Wojciech Witkiewicz, Iwona Bednarz-Misa. "L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs." Cancers 12.9 (2020) 2594