Carcinogenesis: Failure of resolution of inflammation?

Abstract

Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.

Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes

“…A substantial body of evidence demonstrates that chronic, non-resolving inflammation sustains the development and progression of several tumors [1,2]. The unbalanced production of inflammatory mediators and the presence and activation of an inflammatory infiltrate in the cancer microenvironment may be hijacked by tumors to foster their proliferation, survival and migration.…”

Integrated Metabolomics and Lipidomics Analysis Reveal Remodeling of Lipid Metabolism and Amino Acid Metabolism in Glucagon Receptor–Deficient Zebrafish

“…Except for ARA and PC, all other 17 metabolites were increased ( Figure 4 , Supplementary Table 2 ). The products of ARA were eicosanoids, including prostaglandins, leukotrienes, lipoxins, thromboxanes, hepoxilins, isoprostanes, and hydroxyeicostetraenoic acids, which played important roles in organism physiology (Bend and Karmazyn, 1996 ; Sharma and Sharma, 1997 ; Fishbein et al, 2020 ). We found that the metabolites from six classes were increased, including prostaglandins consisting of PGE2 (prostaglandin E2, 0.93), PGG2 (prostaglandin G2, 1.20), 6-Keto-PGF1a (1.54), 6-keto-PGE1 (1.80), and 15-deoxy-PGJ2 (1.76); leukotrienes consisting of LTA4 (leukotriene A4, 1.87), LTB4 (leukotriene B4, 1.75), and 5(S)-HPETE (1.31); lipoxins consisting of LXB4 (lipoxin B4, 1.30), hepoxilins consisting of TXA3 (trioxilin A3, 1.43), and TXB3 (trioxilin B3, 1.21); hydroxyeicostetraenoic acids consisting of 15-OxoETE (2.23), 12(S)-HPETE (1.52), 15(S)-HPETE (1.64), 11,12,15-THETA (1.72), and 12-OxoETE (1.06); and isoprostanes consisting of 8-isoprostane (2.26) ( Figure 4 , Supplementary Table 2 ).…”

Inhibition of drug-metabolizing enzymes by Qingfei Paidu decoction: Implication of herb-drug interactions in COVID-19 pharmacotherapy

“…But for some agents with improved safety profiles or wide therapeutic windows, inhibition of the key P450s responsible for metabolic clearance of these agents may extend the metabolic half-lives and increase the plasma exposure of these P450 substrate-drugs in vivo , which will be beneficial for the patients. Furthermore, some P450s (such as CYP1A and CYP3A) have been validated as the key enzymes participating in the oxidative metabolism of arachidonic acid (AA) and other fatty acids ( Arnold et al, 2010 ; Kroetz and Zeldin, 2002 ), while the oxidative metabolites of AA have been recognized as the key chemical mediators of inflammation ( Tallima and Ridi, 2017 ; Fishbein et al, 2020 ). Thus, potent inhibition on CYP1A and CYP3A by QPD may partially block the formation of the oxidative metabolites of AA, thereby alleviating the systemic inflammation in patients with COVID-19.…”