Free Radical Research in Cancer

Abstract

It can be challenging to find efficient therapy for cancer due to its biological diversity. One of the factors that contribute to its biological diversity are free radicals. Evolutionary, aerobic organisms evolve in an oxygen atmosphere, improving the energy production system by using oxygen. Oxygen is beneficial, but it can also be detrimental if free radicals are formed [1]. Free radicals, as well as some non-radical species that have oxygen, are reactive oxygen species (ROS). ROS can damage DNA leading to mutations, single, or double-strand breaks [2]. These events, if the cell is unable to repair the damage, are deleterious. If not fatal, these changes in genetic material result in tumor development by losing cell cycle control. Further, these mutations create genetic instability that result in tumor heterogeneity, and thereby increase the possibility of surviving stress conditions. In addition to direct interaction with DNA, proteins, and lipids, ROS are also signaling molecules that take an active part in regulating cellular processes [3,4]. It was previously thought that ROS only damage cells, but we now know that some enzymes primarily produce ROS, and they are not by-products [3]. These are NAD(P)H oxidases (NOX) and they produce ROS in response to inflammatory signaling. This planned production of ROS may play a role in proliferation, as ROS are able to activate signaling pathways, such as mitogen activated-protein kinase (MAPK)/extracellular-regulated kinase 1/2 (ERK1/2), phosphoinositide-3-kinase (PI3K)/protein kinase (Akt), and more, thoroughly reviewed in [3]. An important factor in surviving ROS is the antioxidant system of the cell. The main role of this complex system is to remove the excess ROS. As there are many ROS, there are many different parts of this system acting in a similar or unique way in removing ROS, such as the glutathione system, superoxide dismutase-catalase catalase, thioredoxin system, and small molecules (e.g. vitamin C, vitamin E). In order to ensure the right levels of these enzymes and small molecules, ROS activate several antioxidative transcription factors, such as Nrf2 and the FoxO family. These transcription factors are responsible for activating the majority of antioxidative genes [5][6][7]. Generally, cancer cells have increased amounts of ROS; consequently, they adapt by increasing the antioxidative defense system [8], thereby, strongly linking ROS and antioxidative research.Nevertheless, ROS were at first considered detrimental, and this was used as a therapeutic strategy in fighting cancer. Most of the conventional types of chemotherapy, as well as radiotherapy, are based on ROS production. Unfortunately, this strategy has to eradicate the tumor completely, otherwise the surviving cells adapt and build up their antioxidant systems, as well as other mechanisms (e.g., drug transporters) making themselves resistant. Strategies involving activation/inhibition of signaling pathways (and here, Nrf2 was certainly an attractive target) turned out to be a double-edged sword...

Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis

“…Physiologically, EMT can be observed during embryogenesis, tissue development and wound healing [48]. It is also a common phenomenon during carcinogenesis and can either induce or coexist with various malignancies such as breast cancer, thyroid cancer, cholangiocarcinoma, non-small cell lung carcinoma, colorectal cancer, inflammatory bowel disease or GC [49][50][51][52][53][54][55][56][57][58][59][60]. During the EMT process, ECs undergo a series of biochemical reactions that eventually lead to alterations in the cells' morphology, especially the loss of the polarity of cells [17,61].…”

Synthesis, Characterization and In Vitro Evaluation of Novel 5-Ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones as Possible Anticancer Agents

“…Cancer is a systemic disease and both its internal metabolic and genetic aberrations as well as the efficiency of immunologic protection play a role in tumor development and progression [2]. Chronic inflammation, redox imbalance, metabolic dysfunctions and altered glucose metabolism as well as many other endogenous and exogenous factors play roles in disease biology and define outcomes [3][4][5]. This heterogeneity of cancer requires the application of various approaches to prevention and treatment that may include application of specific small molecules interfering with altered metabolic pathways in cancers, modulation of immune specific small molecules interfering with altered metabolic pathways in cancers, modulation of immune response to transformed cells and precision medicine [6][7][8].…”

“…The class of 5-ene-thiazolo [3,2-b][1, 2,4]triazole-6(5H)-ones bicyclic heteroatom-rich compounds [9] containing a 1,2,4-triazole ring and an enone/chalcone system cross-conjugated through a sulfur atom in the molecule has recently attracted the attention of medicinal chemists due to its diverse biological activities. Some 5-ene-thiazolo [3,2b][1, 2,4]triazole-6(5H)-ones have been studied successfully as potential anti-inflammatory [10][11][12][13][14], analgesic [11,13], antimicrobial [15], antifungal [16], antioxidant [17], anticonvulsant [18,19], antihypertensive [20] and anti-aggregation agents [21] (Figure 1).…”

“…The class of 5-ene-thiazolo [3,2-b][1, 2,4]triazole-6(5H)-ones bicyclic heteroatom-rich compounds [9] containing a 1,2,4-triazole ring and an enone/chalcone system cross-conjugated through a sulfur atom in the molecule has recently attracted the attention of medicinal chemists due to its diverse biological activities. Some 5-ene-thiazolo [3,2b][1, 2,4]triazole-6(5H)-ones have been studied successfully as potential anti-inflammatory [10][11][12][13][14], analgesic [11,13], antimicrobial [15], antifungal [16], antioxidant [17], anticonvulsant [18,19], antihypertensive [20] and anti-aggregation agents [21] (Figure 1). It is worth mentioning that the structural transformation of the carboxylic group into a 5-ene-thiazolo [3,2-b][1, 2,4]triazole-6(5H)-one moiety has been proposed as a bioisosteric replacement or structure optimization pathway for the synthesis of novel derivatives to keep the main pharmacological profile and to reduce/improve toxicity parameters and activity profiles [10,[22][23][24].…”

“…Some 5-ene-thiazolo [3,2b][1, 2,4]triazole-6(5H)-ones have been studied successfully as potential anti-inflammatory [10][11][12][13][14], analgesic [11,13], antimicrobial [15], antifungal [16], antioxidant [17], anticonvulsant [18,19], antihypertensive [20] and anti-aggregation agents [21] (Figure 1). It is worth mentioning that the structural transformation of the carboxylic group into a 5-ene-thiazolo [3,2-b][1, 2,4]triazole-6(5H)-one moiety has been proposed as a bioisosteric replacement or structure optimization pathway for the synthesis of novel derivatives to keep the main pharmacological profile and to reduce/improve toxicity parameters and activity profiles [10,[22][23][24]. In addition to the abovementioned pharmacological features, some 5-ene-thiazolo- [3,2-b][1,2,4]triazole-6(5H)-ones possess promising antitumor properties.…”