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Hindawi Journal of Oncology Volume 2019, Article ID 7462513, 14 pages https://doi.org/10.1155/2019/7462513 Review Article Jesse A. Stoff Integrative Medicine of New York, Post Ave., Suite , Westbury, NY , USA Correspondence should be addressed to Jesse A. Stoff; email@example.com Received 14 September 2018; Accepted 6 January 2019; Published 15 January 2019 Academic Editor: Vincenzo Tombolini Copyright © 2019 Jesse A. Stoff. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Over the years, the treatment of patients with cancer has varied widely as much because of recent advancements in science and medicine as the philosophies that belie their use. is Th paper briefly describes many of the prevailing approaches in use today with an attempt to oer ff some perspective of how to apply these disparate methodologies so that they may be more effectively integrated, resulting in consistently better clinical responses. 1. Introduction 2. Genetic Stabilizers From a perspective of 10,000 feet there are two basic char- As a starting point to help my patients who are fighting acteristics of cancer: genetic instability and the propensity to cancer, there are a few supplements one can use until lab tests metastasize. From those two basic observational characteris- and genetic studies are completed. Once the tests and studies tics, the hallmarks of cancer were derived by Drs. Hanahan are finalized and returned, a more specicfi treatment strategy and Weinberg in 2000 as follows: can be formulated to address the above hallmarks. Each of these supplements has a multitude of beneficial effects, but Self-sufficiency in growth signals chief among them is their ability to stabilize genetics, creating Insensitivity to antigrowth signals the foundation of an integrative anticancer strategy. During Evading apoptosis the course of oncogenesis and tumor progression, cancer cells constitutively upregulate signaling pathways relevant to cell Limitless replicative potential proliferation as a result of any number of genetic mutations. Sustained angiogenesis It is that genetic instability that leads to cancer being cancer Tissue invasion and metastasis. in the rst fi place and it is those mutations which account for the multiple cell lines that compose every tumor. And then the following were added in 2011: First on our list of genetic stabilizers is vitamin D. In Deregulating cellular energetics addition to enhancing DNA repair, vitamin D also induces growth arrest and apoptosis of tumor cells and their nonneo- Avoiding immune destruction plastic progenitors. Cell-based studies show that the active Genome instability and mutation metabolite 1,25 dihydroxyvitamin D is the biologically active Tumor-promoting inam fl mation [1, 2]. form that works through the vitamin D receptor to regulate Based upon the two basic characteristics of cancer, there gene transcription. Vitamin D (D ) is produced from 7- dehydrocholesterol when skin is directly exposed to UVB are nonspecific medicaments that should be considered in light which, in more northern locations, is largely lfi tered out all cases to help stabilize the mutated genetics. Laboratory testing will clarify the ongoing need for these agents and by the atmosphere. Vitamin D is readily sourced from various foods including fish, eggs, caviar (for the gourmets among others in their class. As a starting point, they are a safe and us), some mushrooms, beef liver, and cheese. Regardless of efficacious place to begin therapy. The other hallmarks of cancer will be addressed with the strategies that follow. whether vitamin D comes from the skin or the diet, vitamin 2 Journal of Oncology D is transported through the blood by the vitamin D Binding Another protein aec ff ted by curcumin is Akt (protein Protein (DBP). Once delivered to the liver, vitamin D is kinase B), a serine/threonine kinase. It is a critical enzyme hydroxylated on its side chain to form 25 hydroxyvitamin in signal transduction pathways involved in cell proliferation, apoptosis, and angiogenesis. Curcumin inhibited the phos- D (25OH D). This is a stable metabolite whose serum levels are commonly used to assess vitamin D status. As needed phorylation of Akt in a dose dependent manner leading to and if available, D circulates to the kidneys which is the another pathway of apoptosis. primary site where the active form of vitamin D, 1,25(OH) Curcumin also induces the upregulation of carcinogen- D, is produced through the genomic actions of 1𝛼 ,25(OH) detoxifying enzymes, such as glutathione S-transferases, has via the vitamin D receptor (VDR), and its analogs inhibit antioxidation effects, and suppresses cyclooxygenase which cell cycle progression and tumor cell growth. Mechanisms then reduces the level of inflammation and the stimulation of action range from preventing cell proliferation (cell cycle of cancer stem cells. Real time animal model studies have demonstrated that curcumin also decreased the expression of arrest) in cancer cells to inducing apoptosis or suppressing cell adhesion molecules and growth factors that promote DNA damage response genes, including ATM, ATR, BRCA1, cellular homing and metastasis. It also affords important 14-3-3𝜎 ,DNA-PK, and MGMT; thus, the reduction of a DNA damage response is but a part of the reason for curcumin- antioxidant protection and serves as an immunomodulatory for both the innate and adaptive arms of the immune system induced growth inhibition of cancer cells [14–16]. [3–7]. Sulforaphane (SFN) is an isothiocyanate found in crucif- Next comes indole-3-carbinol and its metabolite 3,3 - erous vegetables such as broccoli, brussel sprouts, cauliflower, diindolylmethane (DIM). They target multiple aspects of and cabbage. Experimentally, in cell cultures and animal cancer cell cycle regulation and survival including Akt-NF𝜅 B models, SFN was shown to be a highly effective chemoprotec- signaling, caspase activation, and cyclin-dependent kinase tive against, carcinogen-induced, and genetic animal cancer activities, stabilize estrogen metabolism, normalize estrogen models, as well as in xenograft transplant models of cancer. The early research focused on the detoxification ability of SFN receptor signaling, reduce endoplasmic reticulum stress, and limit BRCA gene expression. DNA hypermethylation is a to induce phase 2 enzyme pathways. Later studies showed common feature of cancer genetics. When methylation detox that SFN could cause cancer cells to enter G2/M phase arrest and result in apoptotic cell death, with the latter being evi- pathways start to fail, certain regions of the genome will accu- mulate too many methyl groups, such as at CpG promoter denced by caspase-mediated cleavage of poly(ADP-ribose) regions (segments of the DNA involved in DNA and RNA polymerase and increased release of histone-associated DNA transcription); this can lead to increased mutagenesis and fragments from the tumor downstream. Furthermore, it leads eventual cancer development. Much research has demon- to the transcriptional activation of genes including tumor strated how DIM reduced methylation at 5 CpG promoter suppressor genes. The effect on cancer genetics is profound regions. For example, in split population studies, mice given and therapeutically beneficial [17–21]. TRAMP prostate cancer cells were also given DIM. The mice Fish oil rounds out our list of top genetic stabilizing supplements. One of many changes that occur to the can- given the DIM showed a much lower incidence of cancer and metastasis than controls, as well as much higher expression cer cell’s biochemistry and genetics is in the production, of antioxidant/anticarcinogen protective enzymes NQO1 and metabolism, and expression of microRNAs (miRNAs). First discovered in the early 1990s, their importance as a distinct NFR2 in prostate tissues [8–14]. Curcumin, a component of turmeric (Curcuma longa), class of biological regulators was not appreciated for another is a low molecular weight molecule that has antiprolifera- decade. MicroRNAs (miRNAs) are short molecules, just tive activity and inhibits tumor initiation and propagation 21–25 nucleotides long, but can have powerful effects on gene through a variety of pathways. It accomplishes this through expression. More than 2000 miRNAs have been identified including many specific miRNAs that have been found to several epigenetic effects that result in genetic modulation that then changes the expression of several key proteins, some be associated with diseases states including cancer and the of which are the cysteine-aspartic acid proteases (caspases). risk of metastasis. The identification of circulating miRNA specific to metastatic cancer presents a unique opportunity Caspases are a family of enzymes that play an essential role in apoptosis, necrosis, and inflammation. Research for early disease identification and for monitoring disease demonstrates that curcumin activates caspases-3 and -8 burden as a circulating biomarker. For example, abnormal but not caspase-9, indicating that the apoptosis induced in activation of some miRNAs found in the blood, let-151a, cancer cells occurs via a membrane-mediated mechanism. miR-21, miR-155, miR-,145 miR-18a, and miR-16, as well Membrane bound enzymes play other important roles in the as tissue specicfi miRNAs, miR-182, miR-145, miR-21, miR- perpetuation of cancer cells such as the ECTO-NOX 2 system. 155/154, miR-203, miR-213, and miR-7, are oen ft found in p53 (TP53) is a tumorsuppressorgene and is responsible patients aec ff ted by breast cancer. Furthermore, there is a growing body of evidence on the value of miRNAs associated for protecting cells from tumorigenic alterations. Mutational inactivation of p53 is frequently observed in many cancers. with the development of drug-resistance, suggesting their Curcumin selectively increases p53 expression during the values, once targeted, as a potential approach to overcoming chemoresistance. miRNAs that are absorbed into our blood G2 phase of the cell cycle of carcinoma cells and releases cytochrome 𝑐 from mitochondria, which is an essential stream from GMO foods are currently being studied for their requirement for then inducing p53-dependent apoptosis in oncogenic potential, as they are normally foreign to human the cancer cell. biology. Fish oil can modulate the expression of the miRNAs Journal of Oncology 3 including significantly reducing the risk of metastasis and has destroy the tumor(s). Many other strategies are available that many other anticancer eeff cts [22–27]. may be oncolytic and can be used based upon the results Once the basic genetic stabilizers are in place we move of the patient’s biochemical and immune tests as well as a thorough analysis of the intrinsic genetics driving the cancer. on to more specific, integrative, anticancer strategies which are based upon laboratory results, the patient’s history, and The combination of this data allows for an individualized, our clinical experience. Integrative anticancer strategies are integrative therapeutic strategy. There is no clear hierarchy based upon the basic observation that, for a patient to or “best answer for cancer”; it depends upon how the patient develop, a serious cancer multiple systemic abnormalities presents and the targeted therapies available at the time that must be occurring simultaneously: genetically, biochemically, the cancer’s genetics are determined. The “best” strategy to be immunologically, and hormonally, which must be addressed employed is a function of this information and the current from a functional medicine point of view. An effective state of the available technology and agents to address it. Some of those strategies are further discussed below: treatment strategy addresses these issues while applying pressure against the weak points of the cancer, as determined (i) Oncolytic virotherapy through laboratory and genetic testing, to buy the time necessary to reconstitute an effective immune response that (ii) Cytotoxic strategies leads to a durable remission. Assuming that the physician (iii) Immunotherapy has a good understanding of immunology and biochemistry (iv) Biochemical treatments and a thorough, if not specialized, knowledge of oncology, then these strategies can be added to their armamentarium (v) Targeted therapies in a matter ofdays orweeksofworkshops and additional (vi) Antiangiogenesis strategies study. There are a number of anticancer strategies that can (vii) Cancer stem cell suppression be employed; which to use when is a matter of objective data collection balanced by experience. Again, in no particular (viii) Oxidative therapies order, as anyone of them could potentially be the one key (ix) Anti-inflammatory strategies strategy needed for a particular patient to go into remission, (x) Detox strategies generally, multiple strategies are needed and are timed to the changing conditions clinically as treatment progresses. (xi) Nutritional diet strategies (xii) Psychoneuroimmunology 3. Differentiation Therapy (xiii) Targeted genetic strategies Differentiation therapy of cancer is a strategy that goes back (xiv) Hyperthermia. to the late 1980s and employs agents that can induce both morphological changes and suppress abnormal proliferation 4. Oncolytic Virotherapy in a time and dose dependent manner. Through mechanisms and pathways known and unknown many substances have Interest in oncolytic virotherapy, as a treatment strategy, has been found to have this effect including phenylbutyrate waxed and waned for decades. For centuries physicians have (an antineoplaston), dimethyl sulfoxide (DMSO), all-trans observed that, in some lucky cases, if patients with cancer, retinoic acid (ARTA), vitamin D, and epigallocatechin gal- even very advanced cancers, contracted a significant acute late (EGCG). The need for cellular differentiation and the illness, bacterial or viral, sometimes the cancer would go reversion back to normal cellular phenotypes is universal into remission. Building upon these observations, Dr. Coley across all cancers; thus the use of this class of agents is as made a scientific assessment of this phenomenon which he important as the use of substances that stabilize genetics. published in 1891 in the Annals of Surgery. He then set about Phenylbutyrate (PB) is an aromatic fatty acid that is converted to reliably replicate these results by developing a sterile lt fi rate in vivo to phenylacetate (PA) by 𝛽 -oxidation in liver and of bacterial toxins from Strep and Serratia. He gave these kidney mitochondria. The actions of PB as a differentiating toxins to patients with cancer, recorded that in many cases agent are primarily related to its activity as an inhibitor of their tumors would indeed go into remission, and published histone deacetylase. Phenylbutyrate can be given by mouth or his results in 1893. This first consistently useful immunother- IV; EGCG and ARTA are, at this point, only available in oral apeutic strategy was then medically usable until 1963 when forms. DMSO, on the other hand, seems to be effective only changes in the structure and politics of the FDA essentially when given IV. Each agent considered must have been shown made it unavailable. However, the basic observation that a to be effective for the type of cancer being treated before being significant febrile illness (as a sort of internal hyperthermia) included in the therapeutic strategy. Then, depending upon could put a cancer into remission did not go away and the competence of the patient’s digestive system and issues of research began to investigate the use of self-limiting viral IV access, appropriate substances can then be used [28–31]. infections as a way of conquering cancer. There have been Anticancer strategies that build upon genetic stabilizers, many reports, usually of farmers, who had cancer and then hormone blockade, and differentiation agents do not nec- contracted the Newcastle virus from a sick chicken, having essarily put the cancer into a durable remission. They do, their cancer go into remission. But, since the Herpes Simplex however, in many cases slow its rate of growth enough so virus was better understood, at the time, than the Newcastle that the immune system, with support, can catch up to and virus, it was the first to be used in a clinical trial in 1996. 4 Journal of Oncology The virus may infect healthy and cancerous cells but normal dormancy and has been in development for two decades, cells, with their defensive pathways still intact, are able to whereas Insulin Potentiated Therapy (IPT) takes physiologic fight off the infection while the cancerous cell succumb to the advantage of the excessive number of insulin receptors found on the cell surface of cancer cells. Giving insulin just prior to apoptotic triggers of the infection. u Th s the virus becomes oncolytic. Viruses that cause mild and self-limiting infec- the infusion of low dose chemotherapeutic agents, usually in a tions in humans are used and modified to accomplish this. combination designed to intervene at several sites of the cell Treatment with oncolytic viruses results in a combination cycle, causes much less side effects and can hold the cancer of tumor-specific cell lysis together with dynamic immune at bay while buying time to reconstitute an effective immune stimulation, therefore acting as a sort of in situ tumor vaccine. response or integrate another therapeutic strategy. IPT has Oncolytic viruses that are currently used are “engineered” been in development and clinical use since the 1930s and has for optimization of tumor selectivity and enhanced immune been used to help treat other chronic diseases as well [40–48]. stimulation and can be readily combined with other thera- peutic strategies. Their effectiveness has been demonstrated 6. Immunotherapy in many preclinical studies and clinical protocols. A related biological strategy is the use of modified live Immunotherapy is an office based strategy for which they bacteria called Bacteria Mediated Tumor Therapy (BMTT). write very thick books, and in the broadest terms possible The first scientific application of this therapy was with it is a treatment that uses the immune system, in some BCG, or bacille Calmette-Guerin, which was developed as way, to identify, attack, and destroy the cancer. Using the a vaccine for tuberculosis (TB) disease and then found to immune system against cancer can be accomplished through be helpful when instilled into the bladder to gfi ht certain active or passive pathways. As a quick overview, there are types of bladder cancer. More recent developments include over one hundred and eighty-seven cell types identified the use of genetically modified salmonella, clostridium, and within the immune system. It includes the lymphatic sys- the plasmids implanted in Listeria. These treatments are thus tem along with the bone marrow spleen, thymus, and, of far less effective because they are designed to present or bind course, lymph nodes. Cells known as CD4 T cells are the to cancer antigens to make them more immunogenic but they “apparent brains” of the immune system and they coordinate do nothing to address the damaged immune system pathways the central immune response to any serious health threat. that allowed the cancer to occur to begin with [32–39]. Activated B cells become plasma cells and, in most instances, generate an antibody response against bacterial and viral invasion. Lymphokine activated killer cells and cytotoxic T 5. Cytotoxic Cancer Therapy cells respond to viruses and cancer. Suppressor T cells are Cytotoxic cancer treatments are covered by the term used to downregulate the actions of the immune system after chemotherapy and have come to imply the use of agents the threat has been eliminated through negative feedback. that act as intracellular poisons to inhibit mitosis or directly Macrophages are voracious amoeboid-like lymphocytes that induce some sort of cell death. Substances that accomplish eat foreign substances and send a message back to the rest this as a secondary effect through blocking extracellular of the immune system indicating what further immune response is necessary. Macrophages and their cousins, the signals or which act through a specific genetic, enzymatic, or hormonal pathway are excluded from this therapeutic dendritic cells, are involved in all aspects of the immune strategy as they are referred to as targeted therapies and response by initially sending out the alarm that something elsewhere described. Chemotherapeutic agents are character- is amiss. Natural Killer cells are preprogrammed at their istically purified to the point of being a chemical and may birth to destroy virally infected cells, cancer cells, some be of natural origin or synthetically created. The deliberate bacteria and parasites on contact without need for further use of natural, herbal source agents began in the early 1920s, direction from the CD4 cells. Some mushroom extracts including Viscum alkaloids and lectins, and they are still used and the bioengineered nutraceutical AiE10 can increase the today, whereas the first synthetic agent, nitrogen mustard, concentration and activity of natural killer cells. was “discovered accidentally” during World War Two when it The immune response cascade operates according to was observed that it could shrink lymphoma tumors in mice. three directives. The first is to recognize that which is foreign and sound the alarm soon enough to thwart the invader. A few years later it was discovered that alkaloids extracted from the Vinca rosea plant were useful in treating Hodgkin’s Molecules and cell surfaces that are identified as foreign disease, and so a multibillion dollar industry was birthed are referred to as antigens and have the ability to elicit an creating and extracting new substances, helpful in the “war on immunogenic response. The second directive is to respond cancer”. Unfortunately, many of these substances have similar to the alarm with enough of a counterattack to effectively effects on healthy cells, thus creating a multitude of side neutralize the invader quickly. The third directive is to effects and limiting their usefulness. Newer protocols that use remember what happened so that if the same situation were lower doses of these agents, such as metronomic or insulin to arise again, an effective response could be generated faster. potentiated chemotherapy, are showing good results with The length and efficacy of the immune response depend upon far fewer side effects. Metronomic, low dose chemotherapy the “intactness” of the underlying biochemistry. The immune seems to act through several mechanisms including inhibit- response cascade is the ultimate biological information pro- cessing and transfer vehicle designed to define, defend, and ing the growth of new blood vessels, the restoration of an anticancer immune response, and the induction of tumor integrate oneself relative to the environment that surrounds Journal of Oncology 5 us. When there is a miscommunication, disease ensues due to accomplished by increasing collagen synthesis in healthy corruption, misdirection, or a lack of that informational o fl w. tissue so that cancer was less able to spread. Later, in 1972 Immunotherapy is designed to correct, stimulate, direct, or Drs. Cameron and Rotman hypothesized that vitamin C reconstitute an effective anticancer response. could have anticancer action by inhibiting hyaluronidase Active immune therapies include, among other agents, and thereby preventing cancer spread, and this hypothesis IL-2, IFN-g, and IFN-a cytokines to stimulate the TH1 cells, was further supported by Drs. Cameron and Pauling. They pathways, and natural killer cells. Monoclonal antibodies, then published clinical research results of 100 patients with checkpoint inhibitors, that disinhibit an immune response are terminal cancer, in whom conventional therapy was no also an active immunotherapy that seems to be most effective longer considered useful, and who were treated with 10 g of when some support has been given to the immune system vitamin C intravenously for 10 days followed by 10 g orally first. Other active therapies include creating primed dendritic indefinitely. The patients who received the vitamin C were compared to 1,000 retrospective controls who had similar cells (for example, Sipuleucel-T (Provenge)) and natural killer cells and then infusing them into the patient to “patch” holes disease diagnosis and stage, but who did not receive vitamin and reconstitute an effective anticancer response. C or any other definitive anticancer therapy. Those who Passive immunotherapies include the use of infused received vitamin C survived 300 days longer than those who antibodies to bind to cancer cells. Then when natural killer did not receive vitamin C. Many other studies have since cells encounter antibody-coated cells, the latter’s Fc regions been done, with more sophisticated strategies and better long interact with their Fc receptors, releasing perforin and term results of progression free survival, overall survival, and granzyme B to kill the tumor cell. Adoptive T cell therapy is improvements in the quality of life. another passive immunotherapy. Several ways of producing Further research on how vitamin C can be cytotoxic and obtaining tumor targeted T cells have been developed. to cancer cells was first based upon studying the enzymes T cell Infiltrating Lymphocytes (TILs), specific to the tumor responsible for cell death. Low levels of alkaline and acid DNase constitute a characteristic of all nonnecrotic cancer antigens, can be removed from a tumor sample with a core biopsy and then purified with a cell separator or filtered cells in animals and humans. It was found that these enzymes from the blood. Subsequent activation with cytokines and are reactivated at early stages of cancer cell death by vitamin cell culturing is performed ex vivo, and then the results were C (acid DNase) in combination with vitamin K(3) (alkaline reinfused into the patient. Activation can take place through DNase). Specifically, the coadministration of these vitamins gene therapy or by exposing the T cells to tumor antigens in (inanoptimal ratio of 100:1, for C and K(3), respectively) the presence of cytokines. TILs can also be stimulated in vivo produced selective cancer cell death without harm to normal with hypofractionated SBRT to induce an abscopal effect, cells and tissues. Pathology studies indicated that cell death which when achieved can have miraculous results. is produced mainly by a newly discovered process called A new, state-of-the-art passive immunotherapy is the use autoschizis. Several mechanisms have been described as of chimeric antigen receptors (CARs, also known as chimeric leading tosuchacell death induced by vitamins Cand immunoreceptors, chimeric T cell receptors, or artificial T K3 (CK(3)), which included formation of H(2)O(2) during cell receptors) which are bioengineered cell receptors that vitamins redox cycling, oxidative stress, DNA fragmentation, combine a new specificity with an immune cell to target no caspase-3 activation, and cell membrane injury with cancer cells. Essentially, what is done is that specific mono- progressive loss of organelle-free cytoplasm as a result of clonal antibody fractions are grafted onto T cell receptors. The oxidative damage. receptors are referred to as chimeric because they are a fusion In the late 1920s Dr. Otto Warburg was performing of proteins and receptors from different immune sources. ground breaking research on cellular respiration, including CAR-T cell therapy refers to an infusion of such specifically that of cancer cells. He found significant and important transformed cells for targeted cancer therapy. CAR-T cells differences between normal and cancer cells noting that their destroy the cancer cells through several mechanisms such metabolism was largely based on an anaerobic fermentation as having a direct cytotoxic effect and/or stimulating other metabolism due to damaged, malfunctioning mitochondria. cells of the immune system through the release of various This brilliant insight opened the door for several biochem- cytokines and growth factors. Due to the CAR-T cells very ically based anticancer strategies. As a result of unstable narrow specificity, less prominent tumor cell lines can be genetics and an inefficient metabolism, cancer cells oen ft die missed allowing for a future recurrence [49–59]. almost as fast as they multiply accounting for the release of tumor markers into the blood stream and allowing for still other anticancer strategies such as antiangiogenesis to be 7. Biochemical Anticancer Strategies utilized. Since the cells are already unstable, sometimes a little Biochemical anticancer treatments, which include the use of push in the right direction is enough to finish them off. One such strategy is the use of 𝛼 -lipoic acid and hydroxycitrate off-label legend pharmaceuticals, are numerous and growing but a few of them are brieyfl reviewed here. Aside from administered IV and PO, respectively. Two enzymes that are commonly altered during carcinogenesis are pyruvate herbal therapies that stretch back millennia, vitamin C may be the most researched and longest used of the biochemical dehydrogenase (PDH), which is downregulated, and ATP strategies. Historically, in 1954, Dr. McCormick observed citrate lyase, which is overexpressed. Alpha lipoic acid is a cofactor of PDH, while hydroxycitrate is a known inhibitor of that patients with cancer did better when supplemented with vitamin C and wrote that he believed that this was ATP citrate lyase. When hydroxycitrate and 𝛼 -lipoic acid are 6 Journal of Oncology given together, experimentally in cell cultures, a significant and indirect effects. Direct approaches target tumor proteins cytotoxic effect was observed: complete cell death was seen (antigens), enzymes, or genes to alter their signaling, infor- following 8 microM lipoic acid and 300 microM hydroxyc- mation transduction, or expression. Examples of direct acting itrate treatment for 72 h. The combination of alpha lipoic agents include monoclonal antibodies (MoAbs), metallo- acid and hydroxycitrate was then administered to healthy proteinase inhibitors, tyrosine kinase inhibitors, and angio- mice, at doses currently utilized for other indications than genesis inhibitors. Indirect acting agents include hormone cancer; no demonstrable toxicity was observed. In murine receptor blockers and epigenetic modulators. cancer models the combination of these two agents was The first monoclonal antibody approved for clinical use found to be very effective against bladder carcinoma, lung was Rituximab in 1997 as a specific therapy for B-cell cancer, melanoma, and several other cancers with efficacy lymphomas. Since then it has proven effective for several at least similar to conventional combination chemotherapy, other diseases. The use of monoclonal antibodies is currently without the toxicity. However, a major limitation to using the most rapidly growing therapeutic strategy in oncology this combination of 𝛼 -lipoic acid and hydroxycitrate is that and has proven to be remarkably effective with less side eec ff ts they can only be effective if the mitochondria are still than the chemotherapeutic agents that they are replacing. present and/or functional, which is not often the case in the Matrix metalloproteinases (MMPs) inhibitors downreg- most aggressive tumors. The increased intracellular alkalosis ulate or block enzymes that break down connective tissue found in most tumors is a strong mitogenic signal, which is and allow cancers to invade local tissues and metastasize and resistant to most inhibitory signals. Simultaneous correction potentiate angiogenesis. They are a family of zinc-dependent of this alkalosis may prove to be necessary for this strategy endopeptidases that are a driving factor for the progression to be consistently effective on its own. However, studies of cancer and, thus, their activity has a direct bearing on have demonstrated that integrating these two agents with patient prognosis. One of the simplest and earliest MMPs is chemotherapy can give improved short term and long term EDTA which has been shown to also be helpful in slowing or results. stopping the progression of cardiovascular heart disease. ECTO (because of their location on the cell’s surface) - Tyrosine kinase inhibitors block an enzyme that func- NOX proteins comprise a family of NAD(P)H oxidases that tions to transfer a phosphate group from ATP to a cellular exhibit both oxidative and protein disulfide isomerase-like protein and acts as an “on”/“off” switch for many cellular activities. The activity of the NOX enzymes correlates with functions and the expression of various genes that eeff ct rate of cell growth as they are an important pathway for cancer. Phosphorylation of proteins by (tyrosine) kinases is energy production, which helps to determine how rapidly an important mechanism in communicating signals within a cells will divide. Normally, when NOX enzyme activity is cell (signal transduction) and regulating cellular activity, such inhibited, cells fail to enlarge following division and the result as (un)regulated cell division. They can become mutated and is a population of small cells unable to reach the minimum “stuck” in the “off” position and allow unregulated growth of size required for them to divide again. Tumor-associated thecell, such as in thecaseofp53. NOX (tNOX) are novelcellsurface ECTO-NOX proteins Hormone therapy for cancer is one of the major modali- that are critical for the growth and activity of cancer cells ties of targeted therapies used against hormone receptor pos- whose metabolism is dependent on a fermentation process itive cancers and involves the manipulation of some aspects for energy production; thus, tNOX, has been identified of the endocrine system through the administration of exoge- as a target for cell killing (apoptosis) of cancer cells. A nous agents. These medications may inhibit the production of tumor-associated NOX (tNOX) is unregulated, refractory specific hormones or act to block their receptor sites and in to hormonal regulation and growth factor suppression, but doing so will aeff ct the expression of various genes in cancer responds to quinone-site inhibitors. Research has demon- cells causing their growth to slow, stop, or trigger an apoptotic strated that among the most potent and effective inhibitors cycle. Some of these agents include aromatase inhibitors, of tNOX are naturally occurring polyphenols exempliefi d by gonadotropin-releasing hormone (GnRH) analogs that sup- the principal green tea catechin (-)-epigallocatechin gallate press hormone production, hormone receptor antagonists, (EGCG), the vanilloid capsaicin, and the chemotherapy agent selective estrogen receptor modulators (SERMs), antiandro- doxorubicin hydrochloride (Adriamycin). gens, progestogens, and somatostatin analogs [85–92]. There are other biochemically based protocols, but inter- vening in these 3 critical pathways are examples of potent 9. Antiangiogenesis Strategies clinical therapies utilizing CK(3), alpha lipoic acid and hydroxycitrate, and EGCG and capsaicin, respectively. These Antiangiogenesis is oen ft critically important in slowing strategies have proven to be safe and effective in vitro, in the growth of cancer. For tumors to enlarge, they need animal models and in small scale human trials, and should an increased blood supply to deliver the nutrients needed be considered as important allies on the war against cancer to produce new cells. Over 60% of tumors create and [60–84]. release vascular endothelial growth factor (VEGF) which is a key pathway for the induction and growth of new blood vessels. Some of the principle stimuli for this production 8. Targeted Therapies are an anoxic environment, inafl mmatory molecules, and Targeted therapies against cancer fall into several classes oncogenic mutations. Once stimulated, the angiogenic switch of therapeutic agents that act through a variety of direct leads to the cancer cell’s expression of proangiogenic factors Journal of Oncology 7 that increase the tumor’s vascularization such as angiogenin, oxidation is reflected in levels of lipid peroxides and oxidized VEGF, b fi roblast growth factor (FGF), and transforming LDL; finally we come to inflammation for which there are growth factor-𝛽 (TGF-𝛽 ). Agents that inhibit this response a myriad of markers including ESR, CRP, plasma viscosity, range from ammonium tetrathiomolybdate (ATM), which adiponectin, monocyte chemoattractant protein 1 (MCP-1), chelates the copper that these enzymes need as a cofactor, CD40 ligand and lipoprotein-associated phospholipase A(2) to EGCG, monoclonal antibodies, and genetically modified (Lp-PLA(2)), and ferritin to name but a few. Inafl mmation bacteria, among other things. Research in this area is very results from or is triggered by virtually every disease known important and promising as it affects a key pathway needed to man and has cellular pathways, plasma cascades, and for the progression of cancer as clearly demonstrated by 4D acute and chronic markers. Some the markers associated with ultrasound [93–97]. cancer include CRP, IL-6, IL-8, and TNF-alpha. Inflammation can stimulate cancer stem cells as well as more mature tumor cells triggering progression. Inafl mmation is a defense mech- 10. Cancer Stem Cell Suppression anism that serves to protect us from the illnesses and injuries Cancer stem cells (CSCs) mediate tumor initiation and that historically, from an evolutionary point of view, were the progression, and inhibiting them is an emerging new area main causes of death. Inflammatory markers activate the Th2 of research to prevent, stop, and reverse cancer. Oncologic pathway which generates more inflammation. In doing so, in research has established that subpopulations of cells identi- an apparent eor ff t to focus and conserve resources, when the fied by monoclonal antibodies to specific cell surface markers Th2 pathway becomes chronically stimulated by infection, behaved like developmental stem cells in their capacity nutritional deficiency, trauma, stress, or toxins, it suppresses to regrow the human tumors for multiple generations in the Th1 pathway which is the critical pathway of the immune experimental immune-deficient hosts. In all of the cancers system needed to protect us from and fight cancer. studied so far, there is good evidence that CSCs are relatively An important enzyme for the inflammatory response is cyclooxygenase (COX), which is critical for the conversion of resistant to radiation therapy and chemotherapy indicating that novel CSC-targeted therapies are needed. Several path- arachidonic acid to prostaglandins and other Eicosanoids. It ways are promising targets against CSCs including inducing exists as two isoforms: COX-1 and COX-2; COX-1 is consti- their apoptosis, inhibiting stem cell self-renewal to either tutively expressed whereas COX-2 is a highly inducible gene stop their division or to promote their differentiation, or that is activated by cytokines, growth factors, phorbol esters, targeting the CSC milieu that supports them. The anti-CSC oncogens, and chemical carcinogens. COX-2 plays a key role agents are categorized under two broad headings: small- in carcinogenesis as has been demonstrated in numerous and macromolecules with different subclasses such as kinase cancer cell types. Multiple pathways have been proposed to inhibitors and polypeptides. One of the rfi st and safest agents explain how increased COX-2 expression might contribute to be recognized as a CSC inhibitor is Metformin [98–110]. to carcinogenesis including elevated BCL-2 protein levels and inhibition of apoptosis, increased angiogenesis, and enhanced metastatic activity. Suppressing COX-2 activity, or 11. Oxidative Therapies at least not stimulating it, which many chemotherapeutic Oxidative therapies can be an important adjunctive therapy agents do, is an important part of any anticancer strategy. because tumor hypoxia is an adverse factor for a useful Many agents have been identified that suppress COX-2 clinical response to chemotherapy and radiotherapy and activity, which can be assayed in vitro and is reflected clinically in decreased levels of CRP, interleukin-6 (IL- stimulates the activity of cancer stem cells. Oxidative thera- pies are the subject of research and clinical trials. An example 6), P-selectin, matrix metalloproteinase-9 (MMP-9), tumor of an oxidative therapy that directly increases, at least, blood necrosis factor (TNF-𝛼 ), and other inflammatory markers. Some of the anti-inflammatory agents that are helpful against oxygen levels is intravenous ozone therapy. Biochemically CoQ10 has been shown to increase oxygen tension in the cancer include Celecoxib, sh fi oil, eicosapentaenoic acid blood. The effects of both of these and other agents against (EPA) and docosahexaenoic acid (DHA), white willow tree, cancer have been shown to be helpful in a number of clinical curcumin, green tea, pycnogenol, boswellia, resveratrol, cats trials but many of the details are yet to be worked out [111–117]. claw, and capsaicin to name just a few of the most common medicaments [106–128]. 12. Anti-Inflammatory Strategies 13. Detox Strategies Anti-inflammatory strategies are of critical importance against cancer. In 1498 Albrecht Durer created the famous Detox strategies have been used against cancer since time woodcut entitled “The Four Horsemen, from the Apocalypse” immemorial. When confronted with cancer, people have which, in a sense, foreshadowed the epidemic of severe and always (rightfully so) felt the need to “detoxify”. In the chronic diseases that we now face. From a biochemical, past, family history was a key factor in assessing ones risk thousand-foot perspective there are four major processes that for getting cancer. Now, most cancers are environmentally are common pathways for the initiation and promotion of induced with the inducers numbering in the thousands but, cancer. They should be assessed for each patient: glycation can by thetimethat a cancer appearsfrom them, asimpledetox be measured with blood sugar, hemoglobin A1C, and Glyco- strategy is not usually enough to stop and reverse it. However, Mark; methylation can be watched with homocysteine levels; studies have shown that removing, chelating, or neutralizing 8 Journal of Oncology toxins is still helpful in fighting the good fight as most of them immune system might even affect the emotional and rational are shown to initiate or promote cancer through a number of centers of the brain. This would explain, in part, why people pathways including being proinflammatory, hormonal dereg- get irritable when they are sick and why mental capacity (like ulators, and immunosuppressants, or cause direct or indirect in dementia) often deteriorates in parallel with resistance to DNA damage. No one strategy has been shown to be magical disease. but they range from water fasts to Essiac tea, Hoxsey herbal Many recent studies have clearly shown this efi ld to be formulas, Gerson diet, Paleo organic diets, and ketogenic analytically scientific, for example, PMID: 15220929. This diets to name but a few. The common denominators seem study showed the following: to be a low carbohydrate load, organic and plenty of lt fi ered “Thus we show that an epigenomic state of water. Other office based detox strategies include specialized a gene can be established through behavioral massage therapies and Ayurvedic Panchakarma, but to be programming, and it is potentially reversible.” effective they require years of training [129–131]. [137–140] 14. Nutritional Diet Strategies 16. Targeted Genetic Strategies Nutritional diet strategies are usually closely related to detox New cancer genetic breakthroughs are being made nearly strategies like two sides of the same coin. Whereas detox seeks on a daily basis. These new discoveries demonstrate the to remove something from the body, nutritional strategies increasingly important role of biomarker analysis and tumor add specicfi nutrients or agents to make up for a decfi iency prolin fi g, and how they play in improving progression free or stimulate an enzyme pathway. Clinical deficiencies can be survival and overall survival through personalized cancer absolute or relative. An absolute nutritional deficiency occurs care. Not only do the genetic mutations frequently lend when someone is not consuming a diet with the needed nutri- themselves to a targeted therapy but they can provide ent(s) or there is a malabsorptive issue with their digestive broader information about DNA mismatch repair (MMR), tract. A relative nutritional deficiency occurs when they are microsatellite instability (MSI), and the tumor mutational consuming the appropriate nutrients but they are “burning” burden (TMB). MMR is a strand specific system for rec- them faster than they are absorbing them. For example, ognizing and repairing erroneous insertion, deletion, and vitamin C requirements increase as the body is under higher misincorporation of nucleotides that can arise during DNA levels of stress: mental, emotional, or physical. If there are replication, as well as repairing some forms of DNA damage nutritional deficiencies, then the underlying enzymes will that can occur from toxin and radiation exposure. MSI is falter, and since the basis of a functional immune system is the condition within the cancer of genetic hypermutability an intact biochemistry, an eeff ctive immune response will (predisposition to mutation) that results from the impaired fail. Doing blood tests for nutrients is thus very important at DNA mismatch repair (MMR) system. The presence of MSI the onset of treatment and periodically throughout its course accounts for the multiple cell lines that comprise every cancer. [132–136]. The DNA mutations lead to the production of abnormal proteins and provides phenotypic evidence that MMR is 15. Psychoneuroimmunology not functioning normally. The more abnormal the proteins produced are, the higher the TMB is and the easier it will be Psychoneuroimmunology is new efi ld of medical prac- for the immune system to identify and attack the cancer cells. tice that takes advantage of the observation that the This correlates to a better clinical response to immunotherapy (neuro)endocrine system plays a critical role in resurrecting assuming that the immune system’s infrastructure and bio- immune defenses. The issue here is one of stress and its chemistry are still intact [141–146]. medical counterpart, psychoneuroimmunology (PNI). In a nutshell, PNI is a scienticfi efi ld of study that views the 17. Hyperthermia immune system as capable of behaving like a bidirectional sensory organ and, therefore, to some degree, under our A useful adjunctive therapy, which is not a strategy unto itself, conscious control and ultimately the key to the mind-body but works well with those described above, is hyperthermia. connection. The powerful healing eeff cts that can occur when Hyperthermia can be used systemically, for example, with the mind is engaged in the battle against cancer have been a far infrared sauna, locally with specialized microwave well documented for over thirty years in over 100 books and equipment, or intralesionally with radio frequency ablation. 9,000+ medical journal articles. The goal of hyperthermia therapy is to raise the temperature ∘ ∘ Well documented research beganinthe 1960swhen Dr. of the cancer to as close to 107 For 42 Casispossible George Solomon discovered that by electrically stimulating without cooking healthy tissues or the patient. At those certain parts of an animal’s brain, its ability to gfi ht infection temperatures it can directly kill or weaken tumor cells by could be improved. By damaging those same parts, its inducing apoptosis, with limited adverse effects on healthy immune function could be impaired. Seeing some indications cells. Due to their abnormal genetics, tumor cell defenses are that macrophages and other defensive cells had specific bind- compromised and, when coupled with their disorganized and ing sites for neurotransmitters (including the mood-altering compact vascular structure, have difficulty dissipating heat endorphins) on their outer membranes, Solomon and many making them susceptible to this directed damage. As a sec- of his contemporaries began to suspect that feedback from the ondary effect, if the cancerous cells do not die outright, they Journal of Oncology 9 may become more susceptible to targeted radiation therapy Acknowledgments and/or chemotherapeutic strategies. 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