Kuehn 2018 Biochem Pharmacol
|Kühn B, Brat C, Fettel J, Hellmuth N, Maucher IV, Bulut U, Hock KJ, Grimmer J, Manolikakes G, Rühl M, Kühn A, Zacharowski K, Matrone C, Urbschat A, Roos J, Steinhilber D, Maier TJ (2018) Anti-inflammatory nitro-fatty acids suppress tumor growth by triggering mitochondrial dysfunction and activation of the intrinsic apoptotic pathway in colorectal cancer cells. Biochem Pharmacol 155:48-60.|
Kuehn B, Brat C, Fettel J, Hellmuth N, Maucher IV, Bulut U, Hock KJ, Grimmer J, Manolikakes G, Ruehl M, Kuehn A, Zacharowski K, Matrone C, Urbschat A, Roos J, Steinhilber D, Maier TJ (2018) Biochem Pharmacol
Abstract: Nitro-fatty acids (NFAs) are endogenously occurring lipid mediators exerting strong anti-inflammatory effects and acting as anti-oxidants in a number of animal models of inflammation. These NFA effects are mediated by targeting important regulatory proteins involved in inflammatory processes, such as 5-lipoxygenase, soluble epoxide hydrolase, or NF-κB. In the present study, we investigated the anti-tumorigenic effects of NFAs on colorectal cancer (CRC) cells in cell culture-based experiments and in a murine xenograft model of human CRC. We could show that 9-NOA suppresses the viability of CRC cells (HCT-116 and HT-29) by inducing a caspase-dependent apoptosis via the intrinsic apoptotic pathway. Co-treatment with the pan-caspase inhibitor Q-VD-OPH counteracted the NFA-mediated apoptosis in both cell lines. Furthermore, NFAs affected the cell cycle transition and reduced the oxygen consumption rate (OCR) immediately. On the contrary to their well-known anti-oxidative properties, NFAs mediated the generation of mitochondrial oxidative stress in human CRC cells. Additionally, similar to the cytostatic drug mitomycin, 9-NOA significantly reduced tumor growth in a murine xenograft model of human colorectal cancer. In contrast to the established cytostatic drug, 9-NOA treatment was well tolerated by mice. This study delivers a novel mechanistic approach for nitro-fatty acid-induced inhibition of CRC cell growth by targeting mitochondrial functions such as the mitochondrial membrane potential and mitochondrial respiration. We suggest these naturally occurring lipid mediators as a new class of well tolerated chemotherapeutic drug candidates for treatment of CRC or potentially other inflammation-driven cancer types.
Labels: MiParea: Respiration, mt-Medicine Pathology: Cancer Stress:Cell death Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell, Other cell lines Preparation: Intact cells
Regulation: Fatty acid Coupling state: LEAK, ET Pathway: CIV HRR: Oxygraph-2k