1. Introduction

Cancer is one of the most burdensome illnesses for humans in the present century, representing a significant public health problem, killing more patients than cardiovascular diseases, and provoking an enormous social impact [1]. The disease gives rise to an enormous economic

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

cost and human sorrow [2]. In the first instance, all cancers can be prevented. However, 70% of worldwide cancer mortality arises in low-income countries and it is predicted that the number of deaths will grow from 5.5 to 8.9 million by 2030 [3]. In general, researchers expect that there will be 21.7 million new cancer patients and more than 13 million cancer deaths, purely from population growth extrapolation [4]. Notwithstanding this, to develop cancer takes many years because this disease is a syndrome of the adult age. The burden of cancer is increasing due to the growing and aging population and because of unhealthy behaviors, such as smoking, alcohol consumption, unhealthy eating, stress, and physical inactivity [5]. Nevertheless, cancer is a slow and devious killer; almost all cancers might be circumvented through prevention, early detection, and treatment [2]. When cancer has been diagnosed, depending on the kind of cancer, treatment involves surgery, radiotherapy, chemotherapy, and immunotherapy, among others, whose success depends on an assortment of factors. Therefore, the development of successful strategies against cancer can be achieved only through an in-depth understanding of the fundamental biological mechanisms that provoke it. With cancer, we are referring collectively to a considerable number of diseases described by an uncontrolled proliferation of genetically altered cells, generating tumors that can metastasize and invade whole organisms, eventually killing the patient [6]. This means that the best knowledge concerning cancer genesis is needed, focusing on preventive and new tailored forms of treatment. This knowledge will be possible through a multidisciplinary effort, where mathematics and physics collaborate with oncologists, molecular biologists, bioinformatics, and many other disciplines to improve the traditional biological method, enriching it with the implementation of new forms and tools of analyses that permit the acceleration of regulatory barriers in health systems that streamline the implementation of new successful therapeutic strategies [7]. In our research group, we have implemented the use of an ELF-EMF to study hepatocarcinogenesis in its early stages to assess its cytoprotective effect, both experimentally and theoretically. We proposed that it is possible to deter the carcinogenic process induced by chemical carcinogens in the early stages during enzymatic procarcinogen activation by CYP450 through the modulation of charge migration in the electron transfer reactions involved in oxidation [8, 9]. This has been achieved by modulating the magnetic sensitivity of short-lived RP intermediaries produced during the catalytic cycle using ELF-EMF. In this chapter, we review the experimental and theoretical findings found by our research group within the context of the current knowledge on the cytoprotective effect of ELF-EMF in the early stages of OS induced by chemical carcinogenesis (ChemCar). We use the term cytoprotection because of the conferred protection that dissuades or modulates, controls, or deviates processes originated from bioactivation of procarcinogens, which avoids or diminishes damage to cells or its molecular components [8, 9]. On the one hand, we describe and discuss the experimental findings of our group on the effect of daily treatment with 4.5 mT (120 Hz) of ELF-EMF. The early stages of OS in rats with chemically induced hepatocarcinogenesis (ChemIndHep) employed the modified resistant hepatocyte model (MRHM) with Fischer rats 344 [10]. Otherwise, as the molecular mechanisms responsible for this effect are still unclear, we developed a quantum mechanical model based on the RPM and the Haberkorn approximation to explain the experimental effects of ELF-EMF on the free radicals produced in the early stages of ChemIndHep [8]. It is plausible to assume that, through the employment of RPM using ELF-EMF, we modulated the RP intermediates involved in free radical generation (as has been reported for other

reactions [11]). Then, directing them towards lower energetic states in such a way that the activation of oxidative products diminished, and the electrophile damage to cells is reduced [9]. Thanks to this multidisciplinary analysis, we can understand the carcinogenic chemical process based on the behavior of charged particles generated during the enzymatic activation of the procarcinogen, that is, when the DNA still has not yet been damaged in the early stages of carcinogenesis [8, 9]. The results of this work allow us to advertise the basis for the design of tailored therapeutic strategies or clinical applications of ELF-EMF as a coadjutant in the treatment of several diseases related to oxidative damage as occurs in cancer [8, 9]. The importance of the use of ELF-EMF-based therapies is precisely their low cost, safety, effectiveness, and their implication on the homeostasis of the biological systems (BS). We can use them in several treatments, such as chronic ulcer healing [12–14], diabetic foot treatment [15], epilepsy treatment, and vascular permeability in the rat brain [16], among others. In the scientific literature, they have been employed in many fields, and the older applications were in the bone regeneration. However, with the problem that concerns us, we can find many examples. (1) Cells of human colon adenocarcinoma exposed to ELF-EMF of 1.5 mT (1 Hz) during 360 min, diminishing in growth [17, 18]. (2) PC-12 cells exposed to ELF-EMF of 50 Hz at several intensities and durations show a decrease in the proliferation rate and their morphological differentiation [18, 19]. (3) Patients with a mean age of 60 years and with stage IV tumors were enrolled in a pilot study. The patients were exposed for 5 days/week over 4 weeks in two different schedules of exposure: one daily for 20 min (four patients) and one daily for

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

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1. Introduction 2. Carcinogenesis 2.1 ChemCar 2.2 Carcinogens 2.3 Metabolization

2.4 The catalytic cycle of CYP450 3. Experimental findings 3.1 Hepatocarcinogenesis

3.3 Experimenal setup 3.4 Experimental results 4. Theoretical findings 4.1 Fundamental facts 4.2 The model

4.2.1 Haberkorn approach 4.2.2 Quantum measurements 4.2.3 Results on hepatocytes

5. Conclusions

Table 1. Contents of the chapter.

3.2 Nrf2 transcriptional factor + ELF-EMF

reactions [11]). Then, directing them towards lower energetic states in such a way that the activation of oxidative products diminished, and the electrophile damage to cells is reduced [9]. Thanks to this multidisciplinary analysis, we can understand the carcinogenic chemical process based on the behavior of charged particles generated during the enzymatic activation of the procarcinogen, that is, when the DNA still has not yet been damaged in the early stages of carcinogenesis [8, 9]. The results of this work allow us to advertise the basis for the design of tailored therapeutic strategies or clinical applications of ELF-EMF as a coadjutant in the treatment of several diseases related to oxidative damage as occurs in cancer [8, 9]. The importance of the use of ELF-EMF-based therapies is precisely their low cost, safety, effectiveness, and their implication on the homeostasis of the biological systems (BS). We can use them in several treatments, such as chronic ulcer healing [12–14], diabetic foot treatment [15], epilepsy treatment, and vascular permeability in the rat brain [16], among others. In the scientific literature, they have been employed in many fields, and the older applications were in the bone regeneration. However, with the problem that concerns us, we can find many examples. (1) Cells of human colon adenocarcinoma exposed to ELF-EMF of 1.5 mT (1 Hz) during 360 min, diminishing in growth [17, 18]. (2) PC-12 cells exposed to ELF-EMF of 50 Hz at several intensities and durations show a decrease in the proliferation rate and their morphological differentiation [18, 19]. (3) Patients with a mean age of 60 years and with stage IV tumors were enrolled in a pilot study. The patients were exposed for 5 days/week over 4 weeks in two different schedules of exposure: one daily for 20 min (four patients) and one daily for


Table 1. Contents of the chapter.

cost and human sorrow [2]. In the first instance, all cancers can be prevented. However, 70% of worldwide cancer mortality arises in low-income countries and it is predicted that the number of deaths will grow from 5.5 to 8.9 million by 2030 [3]. In general, researchers expect that there will be 21.7 million new cancer patients and more than 13 million cancer deaths, purely from population growth extrapolation [4]. Notwithstanding this, to develop cancer takes many years because this disease is a syndrome of the adult age. The burden of cancer is increasing due to the growing and aging population and because of unhealthy behaviors, such as smoking, alcohol consumption, unhealthy eating, stress, and physical inactivity [5]. Nevertheless, cancer is a slow and devious killer; almost all cancers might be circumvented through prevention, early detection, and treatment [2]. When cancer has been diagnosed, depending on the kind of cancer, treatment involves surgery, radiotherapy, chemotherapy, and immunotherapy, among others, whose success depends on an assortment of factors. Therefore, the development of successful strategies against cancer can be achieved only through an in-depth understanding of the fundamental biological mechanisms that provoke it. With cancer, we are referring collectively to a considerable number of diseases described by an uncontrolled proliferation of genetically altered cells, generating tumors that can metastasize and invade whole organisms, eventually killing the patient [6]. This means that the best knowledge concerning cancer genesis is needed, focusing on preventive and new tailored forms of treatment. This knowledge will be possible through a multidisciplinary effort, where mathematics and physics collaborate with oncologists, molecular biologists, bioinformatics, and many other disciplines to improve the traditional biological method, enriching it with the implementation of new forms and tools of analyses that permit the acceleration of regulatory barriers in health systems that streamline the implementation of new successful therapeutic strategies [7]. In our research group, we have implemented the use of an ELF-EMF to study hepatocarcinogenesis in its early stages to assess its cytoprotective effect, both experimentally and theoretically. We proposed that it is possible to deter the carcinogenic process induced by chemical carcinogens in the early stages during enzymatic procarcinogen activation by CYP450 through the modulation of charge migration in the electron transfer reactions involved in oxidation [8, 9]. This has been achieved by modulating the magnetic sensitivity of short-lived RP intermediaries produced during the catalytic cycle using ELF-EMF. In this chapter, we review the experimental and theoretical findings found by our research group within the context of the current knowledge on the cytoprotective effect of ELF-EMF in the early stages of OS induced by chemical carcinogenesis (ChemCar). We use the term cytoprotection because of the conferred protection that dissuades or modulates, controls, or deviates processes originated from bioactivation of procarcinogens, which avoids or diminishes damage to cells or its molecular components [8, 9]. On the one hand, we describe and discuss the experimental findings of our group on the effect of daily treatment with 4.5 mT (120 Hz) of ELF-EMF. The early stages of OS in rats with chemically induced hepatocarcinogenesis (ChemIndHep) employed the modified resistant hepatocyte model (MRHM) with Fischer rats 344 [10]. Otherwise, as the molecular mechanisms responsible for this effect are still unclear, we developed a quantum mechanical model based on the RPM and the Haberkorn approximation to explain the experimental effects of ELF-EMF on the free radicals produced in the early stages of ChemIndHep [8]. It is plausible to assume that, through the employment of RPM using ELF-EMF, we modulated the RP intermediates involved in free radical generation (as has been reported for other

42 Vitamin E in Health and Disease

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 content.

carcinogenesis. The initiation stage is characterized by an irreversible dose-dependent genetic change that predisposes normal cells to evolve into a malicious and immortal state [27]. During initiation, cells are induced to proliferate, but not differentiate [33], inheriting mutations and thus producing initiated daughter cells. In the promotion stage, the initiated cells are clonally selected to expand through an increase in cell proliferation or by a decrease in cell death, the so-called apoptosis process [30]. Although promoter stimuli do not interact directly with the DNA, they can be damaged indirectly by OS, and gene expression can be altered by epigenetic mechanisms. Nevertheless, it is considered that promotion is a reversible stage because the elimination of the promoter produces regression in cell proliferation maybe by apoptosis [33]. Lesions in both initiation and promotion stages are yet to be considered as preneoplastic ones or benign neoplasias [32]. However, in the irreversible third state, they are transformed into malignant lesions, i.e., progression. Cell proliferation independent of stimulus characterizes this stage: faster growth, invasion, metastasis, and morphological, biochemi-

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

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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,

cal, and metabolic changes in transformed cells [33].

2.2. Carcinogens
