2.2. Carcinogens

70 min (seven patients). The results showed that patients do not present side effects. Furthermore, this setup evidenced that humans exposed to ELF-EMF with determinate physical characteristics have a safety profile and with excellent tolerability to the treatment [18, 20]. (4) Patients with advanced hepatocellular carcinoma (HCC), stage I/II, were treated with very low levels of EMF modulated at specific frequencies to HCC. The strategy of stimulation was to administer three daily 60 min outpatient treatments until they arrive at disease progression or death. Most patients reported during the treatment the disappearance or diminishing of pain. Four patients presented with a partial response, and 16 patients had stable disease for more than 3 months. This kind of treatment represents a safe and well-tolerated procedure and also provides evidence of the anticancer effect in this type of patient [18, 21]. We follow the distribution of the syntactic themes expressed in Table 1 for the development of the chapter's

Carcinogenesis is a slow process categorized by the acquirement over time of accumulated mutations and chromosomal changes caused by impairment in the genome that leads healthy cells to become deregulated [22]. During cancer development, are subjected monoclonal or polyclonal malignant cells [23] to a microevolutionary process [24] accumulating critical mutations in a crucial group of genes involved in cell division, apoptosis, DNA repair, and in other essential genes that control collective cell behavior. However, after some critical mutations in genes that maintain genetic stability in healthy cells, cancer cells turn into the mutator phenotype [25, 26], initiating a cascade of mutations through the genome that produces genetic heterogeneity in tumors [23]. This process provides cancer cells with selective advantages to colonize the patient's organism evading its natural defenses used to handle any cellular attack. Such benefits of neoplastic cells have been called the hallmarks of cancer and include six features: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [27]. Transformed cells, then, instead of behaving altruistically and cooperatively, selfishly ignore any regulating signal and proliferate in an uncontrolled way forming tumors, invading

ChemCar is a multistep process initiated by the electron attack to nucleophilic tissues or molecules, such as DNA, producing mutations that lead normal cells to become unregulated, proliferate, and then turn malignant [8, 9, 28]. Metabolic activation of procarcinogens produces highly reactive chemical species that yield to the overproduction of reactive oxygen and nitrogen species (ROS, NOS), which cause damage to DNA and other biomolecules [29, 30]. The current mutation theory of carcinogenesis considers it to be a complicated process that broadly consists of three phases or stages: initiation, promotion, and progression (for a review see [31–33]). Chemical carcinogens may act together or in sequence to initiate or promote

organs and tissues, and spreading throughout the organism, colonizing it.

content.

2. Carcinogenesis

44 Vitamin E in Health and Disease

2.1. ChemCar

There exist a few different mediators that cause cancer, such as biological and physical types, but cancer induced by chemical agents is more frequent [34]. There are a lot of substances or their mixtures identified as carcinogens in the environment, in the diet, in workplaces, in homes, in cosmetics, in the chemicals employed for food production, and even in drugs for human therapeutic use [35]. It has been considered inclusive that cancer could be prevented just by identifying potentially carcinogenic chemicals and eliminating their subsequent human consumption [32]. However, such a practice does not avoid that patients have another kind of cancer. For this reason, search knowledge concerning the chemical and biological mechanisms of cancer development, mainly at very early stages, will contribute to our better understanding of the true nature of this perplexing sickness [8, 9]. Also, it will offer opportunities to generate better strategies to tackle neoplasia or to interrupt the process [32]. It is known that the earlier the detection and treatment of cancer, the better the probabilities of control, prevention, and cure because treatment will be more effective when cancer cells have not yet invaded nearby tissues or metastasized through the body [8, 9, 36]. Furthermore, it is best to interrupt carcinogenesis as soon as possible, maybe in the preneoplastic stages or, even more, at very early stages when carcinogens or by-products of their metabolism have not yet confronted the DNA. In this manner, it could be possible to prevent the progression of the sickness to the invasive terminal stage. The scenario to be considered to identify what mechanisms are needed to be stabilized, arrested, or even reversed [37] should be based on the correct approach to the chemoprevention field in a multidisciplinary study. Cancer research can involve physics and mathematics using physical, natural, synthetic, or biological agents, and mathematical tools of analyses and simulation in computers to reverse, suppress, or prevent either the initial phases of carcinogenesis or the progression of the premalignant cells to invasive sickness [38]. We use ELF-EMF together with quantum mechanics models to assess cancer. Chemical carcinogens are classified into two groups: (1) direct-acting or primary carcinogens and (2) indirect-acting or procarcinogens [8, 9, 39]. Direct-acting carcinogens are compounds sufficiently reactive and electrophilic that they interact directly with DNA forming adducts and chromosome breakage, fusion, deletion, missegregation, or nondisjunction that lead to genomic damage. Conversely, procarcinogens do not interact directly with the genome until they are metabolically activated, producing genotoxic electrophilic metabolites or ROS. We consider that an essential critical point is the process of activation of chemical procarcinogens in which the proper enzymatic reaction of the substrate produces electrophiles and ROS [8, 9]. CYP450 is responsible for these enzymatic reactions. CYP450 is a family of proteins that share common mechanisms of activation of procarcinogens that result in OS [30, 40]. A particular event in ChemCar is the very origin of reactions in cascades, intermediates, and products, which constitute the insult to cells after procarcinogens have been incorporated into the organism [8, 9]. Thus, downregulation of ROS and NOS could contribute to the prevention of cancer initiation [38].

transference [46], changing the oxidation/reduction potential in the spin state of the heme iron from the low-spin form towards the high-spin form, which is a better electron acceptor. Thus, the electron donor, which could be an iron/sulfur protein or a flavoprotein, reduces the highspin iron(III) heme to the high-spin iron(II) state. This intermediate compound has a singlet ground state and is a resonating mixture of the ferrous and ferric forms. This conjugation requires that the dioxygen will be in a singlet state so that the empty orbital of the oxygen can mix with the second occupied orbital of the iron [46]. It is transferred in the oxygen from the activated CYP450, that is, compound I, to the heteroatom of the substrate. It has been described in the general catalytic mechanism as an odd-electron process, which involves the transfer of one electron or hydrogen atom to generate an intermediate complex that collapses

Cytoprotective Effect of 120 Hz Electromagnetic Fields on Early Hepatocarcinogenesis: Experimental…

http://dx.doi.org/10.5772/intechopen.78642

47

Hepatocellular carcinoma (HCC) is one of the public health enemies in low-income countries like Mexico and Brazil. It represents the fifth cause of death in the economic stage of man and ninth in women [48]. Therefore, it is important that HCC is properly understood. HCC is induced by several factors: environmental, infectious, nutrimental, metabolic, and endocrine. Certain factors such as chronic infection with hepatitis B and C, aflatoxin exposure, excessive consumption of alcohol, tobacco, and polysaturated meat consumption can also increase risk [49]. In fact, HCC is associated with liver cirrhosis and chronic hepatitis. Hepatocarcinogenesis is a complex multifactorial phenomenon that appears with loss of heterozygosity, somatic mutation, methylation, and functional inactivation [49]. The disease has a poor prognosis despite the pathophysiological advances and treatments. Chronic liver disease has an initiation point with intrahepatic inflammation promoting the dysregulation of cellular signaling pathways, triggering cell proliferation, and expanding malignant cells [50]. During this stage OS

The Nrf2 (nuclear factor erythroid 2-related factor 2) transcription factor offers essential protection to cells against OS, binding antioxidant response elements and detoxifying enzymes such as glutathione S-transferase A2 and NADPH quinone oxidoreductase [51, 52]. In normal conditions, Nrf2 is found in cytoskeletal protein Keap1 (Kelch-like ECHassociated protein 1). However, when ROS and electrophiles are present, it is dissociated from Keap1, translocating Nrf2 to the nucleus, activating cytoprotective genes that participate in the electrophile conjugation and the excretion of xenobiotics. Since Nrf2 activates phase I and II enzymes, it can be considered as a target for cancer chemoprotection [53]. However, in recent studies, the beneficial antioxidant activity of Nrf2 has been extended to protect cancer cells, since excessive Nrf2 activity provokes mutations in NFE2L2 or Keap1, avoiding chemotherapy efficiency [52, 54, 55]. Another study gave evidence of Nrf2

by recombination [47].

3. Experimental findings

and metabolic disorders appear.

3.2. Nrf2 transcriptional factor + ELF-EMF

3.1. Hepatocarcinogenesis
