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. 2018 Sep;155:48-60. doi: 10.1016/j.bcp.2018.06.014. Epub 2018 Jun 15.

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.

Keywords: Apoptosis; Cancer; Michael acceptor; Nitroalkene; Nitrooleate; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / metabolism*
  • Anti-Inflammatory Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology*
  • Colorectal Neoplasms / metabolism*
  • Dose-Response Relationship, Drug
  • Fatty Acids / metabolism*
  • Fatty Acids / pharmacology
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitochondria / drug effects
  • Mitochondria / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Fatty Acids