Next Article in Journal
New Insights into Breast and Endometrial Cancers
Next Article in Special Issue
Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer
Previous Article in Journal
Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis
Previous Article in Special Issue
Electroporation-Based Treatments in Urology
Article

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

1
Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland
3
Department of Oncological Surgery, Regional Specialist Hospital, 51-124 Wroclaw, Poland
4
Department of Physiotherapy, Wroclaw Medical University, 51-618 Wroclaw, Poland
5
Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland
6
Research and Development Centre at Regional Specialist Hospital, 51-124 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2594; https://doi.org/10.3390/cancers12092594
Received: 31 July 2020 / Revised: 5 September 2020 / Accepted: 10 September 2020 / Published: 11 September 2020
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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.
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. View Full-Text
Keywords: arginase (ARG); nitric oxide synthase (NOS); dimethylarginine dimethylaminohydrolase (DDAH); protein methyltransferases (PRMT); asymmetric dimethylarginine (ADMA); symmetric dimethylarginine (SDMA); dimethylamine (DMA); metabolic reprogramming; chemoprevention arginase (ARG); nitric oxide synthase (NOS); dimethylarginine dimethylaminohydrolase (DDAH); protein methyltransferases (PRMT); asymmetric dimethylarginine (ADMA); symmetric dimethylarginine (SDMA); dimethylamine (DMA); metabolic reprogramming; chemoprevention
Show Figures

Figure 1

MDPI and ACS Style

Krzystek-Korpacka, M.; Szczęśniak-Sięga, B.; Szczuka, I.; Fortuna, P.; Zawadzki, M.; Kubiak, A.; Mierzchała-Pasierb, M.; Fleszar, M.G.; Lewandowski, Ł.; Serek, P.; Jamrozik, N.; Neubauer, K.; Wiśniewski, J.; Kempiński, R.; Witkiewicz, W.; Bednarz-Misa, I. 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 2020, 12, 2594. https://doi.org/10.3390/cancers12092594

AMA Style

Krzystek-Korpacka M, Szczęśniak-Sięga B, Szczuka I, Fortuna P, Zawadzki M, Kubiak A, Mierzchała-Pasierb M, Fleszar MG, Lewandowski Ł, Serek P, Jamrozik N, Neubauer K, Wiśniewski J, Kempiński R, Witkiewicz W, Bednarz-Misa I. 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. 2020; 12(9):2594. https://doi.org/10.3390/cancers12092594

Chicago/Turabian Style

Krzystek-Korpacka, Małgorzata, 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, and Iwona Bednarz-Misa. 2020. "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, no. 9: 2594. https://doi.org/10.3390/cancers12092594

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop