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#
Clinical Immunologist; 

*Corresponding author: E-mail: drstoff@imofny.org, jessestoff@gmail.com 

 
 

Asian Journal of Immunology 
 
5(1): 1-39, 2022; Article no.AJI.77967 
 

 
 

 

 

A Multimodal Strategic Approach to Integrative 
Oncology 

 
Jesse A. Stoff a*# 

 
a
 Integrative Medicine of New York, 520 Franklin Ave Suite 230 Garden City, NY-11530, USA. 

 
Author’s contribution  

 
The sole author designed, analysed, interpreted and prepared the manuscript. 

 
Article Information 

 
Editor(s): 

(1) Dr. Wagner Loyola, Brazilian Agricultural Research Corporation, Concordia. 
Reviewers: 

(1) Yue Jia, USA. 
(2) Bhalchandra Mirlekar, University of North Carolina at Chapel Hill, USA. 

Complete Peer review History, details of the editor(s), Reviewers and additional Reviewers are available here: 
https://www.sdiarticle5.com/review-history/77967 

 
 
 

Received 10 October 2021  
Accepted 13 December 2021 

Published 15 January 2022 

 
 

ABSTRACT 
 

The term “integrative oncology” can mean particular things to different audiences. For the purposes 
of this article, I intend it to mean the simultaneous use of multiple anti-cancer strategies that can 
have a synergistic effect against the tumor, its microenvironment, and its propensity to metastasize. 
Thereby, having a maximum impact against the cancer with a minimum of side effects for the 
patient to endure. As noted in the references, this paper briefly describes the five prevailing 
evidence-based systematic approaches in use today. Each of these approaches has varying 
degrees of effectiveness which, in my experience, when clinically integrated, produces 
exponentially better efficacy, hence shifting progression-free survival into the possibility of 
increased overall survival and a durable remission. This paper is an attempt to offer some 
perspective of how to apply these disparate methodologies so that they may be more effectively 
integrated, resulting in consistently better clinical responses. 

 

 
Keywords: Integrative oncology; oncology; multimodal strategic; cancer. 
 

1. INTRODUCTION 
 
Cancer, as a disease of our time, has been 
described as a “wound that does not heal” [1] 

because it has a multitude of biochemical 
dysfunctions at its core. However, in order for 
these genetically and phenotypically abnormal 
cells to survive and thrive, the watchdog of the 

Review Article 



 
 
 
 

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body, the immune system, must itself be 
suffering from a number of serious areas of 
structural and functional damage. From a 
perspective of ten thousand feet, there are two 
basic characteristics of cancer: genetic instability 
and the propensity to metastasize. From those 
two basic observational characteristics, the 
hallmarks of cancer were derived by Drs. 
Hanahan and Weinberg in 2000 as follows:  
 
Self-sufficiency in growth signals. Insensitivity to 
antigrowth signals. Evading apoptosis, Limitless 
replicative potential, Sustained angiogenesis, 
Tissue invasion and metastasis. 
 
And then the following were added in 2011:  
 
Deregulating cellular energetics, Avoiding 
immune destruction, Genome instability and 
mutation, Tumor-promoting inflammation

 
[2,3]. 

 
Based upon the characteristics of the cancer, 
there are five common office-based/out-patient 
strategies that we can employ. Each of these 
strategies is made up of a number of tactics 
based upon the unique expressed characteristics 
of the target cancer and the physiological 
individuality of the patient. Those five strategies 
are first, to balance and normalize the 
metabolism of the patient while inhibiting the 
physiology of the cancer. Second, to identify and 
seek to repair areas of damage within the 
structure and function of the immune system. 
Third, to identify actionable genetic and protein 
mutations that are driving the cancer and 
address them. Forth, to employ agents that can 
inhibit, suppress, or destroy the root of the 
problem, the cancer stem cells. And fifth, to 
directly attack the cancer with cytotoxic 
(chemotherapeutic) agents and radiation therapy. 
Utilizing agents that can decisively accomplish 
one of these strategies or that can engage and 
strike two or more of these objectives with less 
toxicity can lead to greater quality and quantity of 
life for our patients. 
 

2. METABOLIC APPROACH 
 

2.1 Biochemical Support of the Patient 
Milieu  

 

Metabolic targeting is the first anti-cancer 
strategy because it lays the foundation for the 
improved response for all of the other strategies 
that follow. In 1498, Albrecht Durer created the 
famous woodcut entitled “The Four Horsemen, 
from the Apocalypse” which, in a sense, 

foreshadowed the epidemic of severe and 
chronic diseases that we now face. From a 
metabolic, thousand-foot perspective, there are 
four major processes that are common pathways 
for the initiation and promotion of cancer. Each of 
which should be assessed for every patient: 
Glycation; which can be easily measured with 
blood sugar, hemoglobin A1C, and GlycoMark; 
Inflammation; for which there are a myriad of 
markers including ESR, CRP, plasma viscosity, 
adiponectin, monocyte chemoattractant protein 1 
(MCP-1), CD40 ligand and lipoprotein-associated 
phospholipase A(2) (Lp-PLA(2)), and ferritin to 
name but a few; Methylation; which can be 
watched with homocysteine levels; and finally, 
we come to Oxidation; which is largely reflected 
in levels of lipid peroxides and oxidized LDL. 
Current research demonstrates that cancer is 
largely a metabolic disease involving 
disturbances in energy production (deregulating 
cellular energetics) through a shift from 
respiration to fermentation, but this is not the only 
aberrant energy pathway that cancer cells can 
utilize. The genomic instability observed in tumor 
cells, leading to the other recognized hallmarks 
of cancer listed above, is now considered 
downstream epiphenomena of the initial 
disturbance of cellular energy metabolism which 
is often caused by a toxin [4]. The disturbances 
in tumor cell energy metabolism can be linked to 
demonstrated abnormalities in the structure and 
function of and within the mitochondria [5-7]. 
Extrapolating upon this research we come to 
several conclusions for therapeutic intervention. 

 
Glycation starts with diet. Diet has been 
recognized and is now accepted by mainstream 
medicine as a viable strategy for minimizing the 
risk of getting cancer

 
[8-10]. Furthermore, “a 

higher frequency of organic food consumption 
was associated with a reduced risk of cancer”

 

[11]. A proper diet can address issues of 
nutritional deficiency and some toxin exposure 
while supplying necessary anti-oxidants and 
helping to manage glycation (while hopefully 
being delicious). When we apply a dietary 
strategy to someone with cancer, while 
recognizing the dysregulated metabolic 
mitochondrial foundation of the tumors, we come 
to a low carbohydrate/ketogenic diet. Because 
cancer is biochemically dependant upon sugar to 
maintain its fermentation metabolism, depriving it 
as much as possible, of sugar will further 
destabilize the cancer cells making it easier to 
trigger apoptosis, with the addition of other 
therapeutic agents

 
[12,13]. One of those 

therapeutic agents is Metformin. In addition to 



 
 
 
 

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lowering blood sugar levels and thus minimizing 
the fuel source for cancer cells, Metformin 
interferes directly with cell proliferation and 
supports apoptosis in a non-insulin-mediated 
manner. Accumulated research and clinical 
evidence suggest that Metformin exerts its 
positive effect on the clinical course of neoplastic 
diseases, primarily through the stimulation of 5' 
AMP-activated protein kinase (AMPK) in 
association with the upstream liver kinase B1 
(LKB1)

 
[14,15]. AMPK is a key cellular energy 

sensor, activation of which by Metformin leads to 
suppression of energy-consuming processes 
such as gluconeogenesis [16,17]. In carcinoma 
cells, the stimulation of AMPK, mediated by 
Metformin, resulted in the inhibition of the 
mTOR/ribosomal S6 kinase pathway and thus 
inhibition of the pathological cell cycle 
progression, cell growth, and angiogenesis

 

[18,19]. This is a particularly important effect 
when there is a mutation of phosphatase and 
tensin homolog (PTEN) which would normally 
downregulate this pathway

 
[20]. 

 
Inflammation is another metabolic pathway that 
drives cancer, therefore, anti-inflammatory 
strategies are of critical importance against 
cancer [21]. Inflammation results from or is 
triggered by virtually every disease known to 
man and has cellular pathways, plasma 
cascades, and acute and chronic markers. Some 
of the markers associated with cancer include 
CRP, IL-6, IL-8, and TNF-alpha. Inflammation 
can stimulate cancer stem cells as well as more 
mature tumor cells, triggering disease 
progression. Inflammation is a defense 
mechanism that serves to protect us from acute 
inflammatory illnesses (infections) and injuries 
that historically, from an evolutionary point of 
view, were the main causes of death. 
Inflammatory proteins activate the Th2 pathway 
which generates more inflammation. In doing so, 
in an apparent effort to focus and conserve 
resources, when the Th2 pathway becomes 
chronically stimulated by infection, vaccinations, 
nutritional deficiency, sugar, alcohol, trauma, 
stress, or toxins, it suppresses the Th1 pathway 
which is a critical pathway of the immune system, 
needed to protect us from, and fight cancer. 
Cimetidine can help to restore the Th1/Th2 
balance and overcome pro-inflammatory Th2 
dominance [22]. Activation of the Th1 pathway 
and its downstream effector cells results in the 
production of Reactive Oxygen Species (ROS). 
Which are inflammatory molecules that act 
locally to kill cancer cells, so we don’t want to 
negate all inflammatory responses [23]. 

An important enzyme for the inflammatory 
response is cyclooxygenase (COX), which is 
critical for the conversion of arachidonic acid to 
prostaglandins and other Eicosanoids. It exists 
as two isoforms: COX-1 and COX-2; COX-1 is 
constitutively expressed whereas COX-2 is a 
highly inducible gene that is activated by 
cytokines, growth factors, phorbol esters, 
oncogens, and chemical carcinogens. COX-2 
plays a key role in carcinogenesis as has been 
demonstrated in numerous cancer cell types. 
Multiple pathways have been proposed to 
explain how increased COX-2 expression might 
contribute to carcinogenesis including elevated 
BCL-2 protein levels and inhibition of apoptosis, 
increased angiogenesis, and enhanced 
metastatic activity. Suppressing COX-2 activity, 
or at least not stimulating it, which many 
chemotherapeutic agents do, is an important part 
of any anticancer strategy. Many agents have 
been identified that suppress COX-2 activity, 
which can be assayed in vitro and is reflected 
clinically in decreased levels of CRP, interleukin-
6 (IL-6), P-selectin, matrix metalloproteinase-9 
(MMP-9), tumor necrosis factor (TNF-α), and 
other inflammatory markers. Some of the anti-
inflammatory agents that are helpful against 
cancer include Celecoxib, fish oil, 
(eicosapentaenoic acid (EPA) and 
docosahexaenoic acid (DHA)), white willow tree, 
curcumin, green tea, pycnogenol, Boswellia, 
resveratrol, cats claw, and capsaicin to name just 
a few of the most common medicaments[24-49]. 
 
Methylation seems to still be incompletely 
understood when it comes to cancer. On the one 
hand, people with the fairly common 
methylenetetrahydrofolate reductase (MTHFR) 
mutation are at a higher risk of getting certain 
(and maybe all) cancers [50]. This makes sense 
because that gene affects some of the liver detox 
pathways and when it isn’t working well it can 
lead to known increased risks for cardiovascular 
heart disease, leukemia, breast cancer, colon 
cancer, and many other illnesses [51]. The 
mutation can be tested for and some of its effects 
monitored with homocysteine blood levels. Many 
of the negative effects can be bypassed with 
methylated B vitamins. On the other hand, gene 
expression can be significantly modulated by 
alterations in DNA methylation patterns. 
Methylation within the promoter regions of tumor 
suppressor genes causes their silencing, and 
methylation within the gene itself can induce 
mutational events. These mechanisms may play 
a fundamental role in precipitating the 
development of a large and diverse number of 



 
 
 
 

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human cancers[52]. It is important to monitor 
homocysteine and B vitamin levels while treating 
people with cancer, because overshooting your 
mark may make some cancers worse [53]. When 
a woman is pregnant we give prenatal vitamins 
which are largely B vitamins to stimulate the cell 
growth of the fetus, and when you’re fighting 
cancer you don’t want to do that. However, it is 
important to note that, B vitamin deficiencies will 
inhibit many immune functions that are 
desperately needed for the fight [54]. Nothing 
about fighting cancer is easy, getting biochemical 
moieties to and maintaining them within the 
normal range is a safe bet, from a metabolic 
perspective. 
 

Oxidation, like the rest of metabolic activity, is 
also a bit of a double-edged sword when it 
comes to cancer. Oxidative stress is caused by 
many things including; obesity, high fat diet, 
sugar, the chemicals in processed foods, 
radiation, smoking, alcohol, Covid-19, 
environmental pollution and chemicals, etc., etc., 
etc..(i.e. life) [55]. Damage from oxidative stress 
occurs when the cells and tissues are unable to 
keep up with harm done by the free radicals that 
are generated from the above, and other causes. 
A free radical is an atom, molecule, or ion that 
has an unpaired valence electron that can bind 
to, and damage, DNA and messenger molecules 
but is normally kept in check by the body’s store 
of anti-oxidants. This damage is carcinogenic. 
Anti-oxidants can mitigate oxidative stress and 
are found in vegetables such as broccoli, 
spinach, carrots, cabbage, and vitamins C, E, D, 
A, etc., etc., etc... Uncontrolled oxidative stress 
can activate a variety of transcription factors 
including nuclear factor kappa-light-chain-
enhancer of activated B cells (NF-κB), activator 
protein 1 (AP-1), tumor protein 53 (p53),  
Hypoxia-inducible factor-1a (HIF-1α), 
Peroxisome proliferator- activated receptor 
gamma (PPAR-γ), β-catenin/Wnt, and nuclear 
factor erythroid 2–related factor 2 (Nrf2). 
Activation of these transcription factors can lead 
to the expression of over 500 different genes, 
including those for growth factors, inflammatory 
cytokines, chemokines, and cell cycle regulatory 
molecules. Activation of these molecules by 
oxidative stress stimulates inflammatory 
pathways leading to the transformation of a 
normal cell to a tumor cell, increases tumor cell 
survival, proliferation, chemoresistance, 
radioresistance, invasion, angiogenesis and 
supports cancer stem cell survival [56]. On the 
other side of the sword, the production of 
oxidative reactive oxygen species (ROS) is 

required for the function of another major effector 
of the innate immune system, Natural Killer (NK) 
cells—hydroxyl radical production is responsible 
for NK cells-mediated cytolysis, by promoting the 
secretion of cytotoxic factors from NK cells 
granules [57-62]. ROS can promote 
carcinogenesis by inducing genetic mutations, 
activating oncogenes, and raising oxidative 
stress, which can stimulate cell proliferation, 
survival, and reduce apoptosis. Over the past 
few decades, natural compounds have attracted 
attention as potential cancer therapies because 
of their ability to maintain cellular redox 
homeostasis with minimal toxicity. Research and 
clinical studies show that bioactive dietary 
polyphenols exert antitumor effects by inducing 
ROS-mediated cytotoxicity in cancer cells. These 
bioactive compounds also regulate cell 
proliferation, survival, and apoptotic and 
antiapoptotic signaling pathways [63]. Amongst 
many other examples, this is demonstrated in the 
ability of Aronia melanocarpa to increase the 
expression and activity of p53 and p73 that leads 
to the down-regulation of the expression of cyclin 
B1, which contributes to the cell cycle arrest of 
cancer cells [64-66]. 

 
Some commonly used anti-cancer agents 
include: 
 

Glycation 

Metformin [67,68] 
Berberine [69,70] 
Azadirachta indica (neem) [71,72] 

Inflammation 

Celebrex [73] 
Curcumin [74,75] 
Grape Seed Extract [76,77] 
Cimetidine [78] 
Viscum [79] 

Methylation 

Decitabine [80] 
EGCG [81] 

Oxidation 

DMSO [82] 
Raloxifene [83] 
Vitamin C and MANY other vitamins and 
minerals [84] 

 

2.2 Biochemical Targets of the Tumor: 
The Micro-environment 

 
A closer look at the cancer itself demonstrates 
that by corrupting and recruiting non-malignant 
cells in the area, the tumor has created its own 
biochemical tumor microenvironment (TME) 



 
 
 
 

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suitable for its self-protection and propagation 
[85]. Many different cell types, besides the 
cancer, can be found in the TME including; 
adipocytes, fibroblasts, dendritic cells, 
lymphocytic endothelial cells, myeloid-derived 
suppressor cells, pericytes, tumor-associated 
macrophages, tumor-associated neutrophils, and 
vascular endothelial cells, to name but a few [86]. 
Other cells to be found in TME include T-cells, 
NK cells, NKT cells, and some B-cells that are 
there to fight the good fight. Dendritic cells and 
macrophages found just outside of the TME are 
also engaged in the battle against the cancer, but 
if consumed by the tumor, seem to become 
corrupted and aid in its survival [87]. The 
dynamic interactions of the cancer cells with the 
stromal cells (cellular part) and extracellular 
matrix (ECM) components (non-cellular 
structures) are essential for stimulating the 
multiple cell lines of the cancer, as well as its 
clonal evolution and propensity to develop 
multidrug resistance, resulting in cancer cell 
progression and metastasis [88]. The ECM holds 
cells, tissues, and organs together and maintains 
the three-dimensional structure of the body. For 
a cancer cell to metastasize from the primary 
tumor to other organs, it must locally degrade the 
ECM components that are the physical barriers 
to cell motility. Cancer cells build, shape, and 
recruit support for their TME through the release 
of many different types of molecules including; 
matrix remodeling enzymes, mediators of 
inflammation (which can stimulate the activity of 
the matrix metalloproteinases), cytokines, cell-
free DNA (cfDNA, which we can now test for [89] 
chemokines, growth factors, exosomes, and can 
facilitate horizontal gene transfer [90]. The 
reciprocal and self-supporting cell-cell/ECM 
interaction forces the expression of new 
phenotypes of non-cancer cells that promotes 
the development and invasion of the cancer at 
large [91].  
 
Trying to bring order back to such a maelstrom is 
the focus of a great deal of research at this time 
as it is an important piece of a durable remission. 
Targeting the TME has proven to be no easy feat 
and has been based upon trying to undermine 
the major components of it. Starting with the 
milieu itself, it has long been noted that the TME 
is more acidic than normal tissue in the local 
area, while the intracellular Ph is often more 
alkaline [92]. However, just trying to inject the 
TME with sodium bicarbonate does not seem to 
be a reliably effective treatment because the 
active biological processes that created the 
abnormal gradient, to begin with, will rebound 

and increase its level of activity to re-establish its 
supportive environment. Combining sodium 
bicarb with cytotoxic agents seems to offer a 
better strategy [93,94]. Changing the electro-
chemical gradient of the TME, and thus the Ph, 
with an electrical current has also shown to be 
effective in some cases [95-97]. 
 
Another strategy that targets the TME is to inhibit 
the matrix metalloproteinases(MMPs) that 
degrade the extracellular matrix (ECM) 
components that then allows for local metastasis. 
Research has identified many substances that 
can inhibit these MMP’s. Resveratrol, a 
polyphenol present in various plants, food 
products, red wine, and grapes, has been 
demonstrated to suppress MMP-2 and MMP-9 
[98]. Additionally, resveratrol can inhibit the 
expression of  Vascular endothelial growth factor 
(VEGF) and act as an anti-inflammatory agent 
[99]. Agents derived from marine sources have 
also been found to inhibit MMP’s including 
various plant and animal sources of saccharoids, 
flavonoids, polyphones, and fatty acids but thus 
far, few have been shown to be reliably clinically 
effective [100]. One agent that did make it into 
clinical trials was AE-941/Neovastat. According 
to the National Cancer Institute, “shark cartilage 
extract, AE-941 competitively inhibits the binding 
of pro-angiogenic vascular endothelial growth 
factor (VEGF) to its cell receptor, thereby 
inhibiting endothelial cell proliferation”. This 
agent also inhibits matrix metalloproteinases 
(MMPs), but at this time, there are no clinical 
studies involving its use [101]. Chlorella, a 
protein extract from algae has also been shown 
to have MMP’s inhibitory properties [102]. Tissue 
inhibitors of metalloproteinases (TIMP’s) 
naturally impede the activity of the MMP’s and its 
the imbalance between the activation and 
inhibition of them that is largely responsible for 
the progression of a tumor’s growth [103]. Other 
polyphenols that can inhibit the MMP’s are 
quercetin, epigallocatechin gallate, and 
curcumin. They act as dynamic antioxidants, and 
are able to interact with cell-signaling pathways, 
modulating gene expression in three different 
ways: i) influencing the activity of transcription 
factors, ii) epigenetically, modulating microRNAs, 
and iii) having an anti-inflammatory effect, all of 
these actions serve to down-regulate MMP 
activity [104]. Combining polyphenols with amino 
acids that are used in the production of the ECM 
along with vitamin C which, too, is critical for 
ECM support, has been shown to be an effective 
strategy for slowing the progression of tumors. 
Their combined anti-cancer effects include 



 
 
 
 

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inhibition of: metastasis, tumor cell growth, matrix 
metalloproteinase secretion and activity, local 
invasion, angiogenesis, as well as induction of 
apoptosis of the cancer cells [105-108]. This 
combination has been effective both in vitro and 
in vivo against many different cancers and 
cancer cell lines including ovarian, melanoma, 
squamous cell, and others in a dose-dependant 
curve [109]. A chief problem for the use of 
polyphenolic compounds against cancer is their 
low bioavailability [110]. Different types of 
formulations have been designed to address this 
issue, nanonization being one of the most 
notable approaches among them. Variations of 
nanoformulations are designed to be effectively 
transported through the relevant biological 
barriers to the targeted organs, tissues, and 
cells. Research on natural polyphenols as 
bioactive agents include: resveratrol, curcumin, 
quercetin, epigallocatechin-3-gallate, chrysin, 
baicalein, luteolin, honokiol, silibinin, and 
coumarin derivatives, which have shown efficacy 
in a dose-dependent manner and may result in 
better treatments of cancer [111]. 
 
The tumor microenvironment, created by the 
cancer, further supports its dysfunctional growth 
and ability to metastasize through epigenetic 
changes. Epigenetic changes are heritable but, 
unlike genetic nucleotide modification, are 
reversible and therefore targetable as part of an 
oncolytic therapy. A variety of epigenetic 
mechanisms have been identified that can 
induce and/or support a cancer, such as: 
silencing of tumor suppressor genes, activation 
of oncogenes by altered cytosine phosphorus 
guanine (CpG) island methylation patterns, 
histone modifications, and dysregulation of DNA 
binding proteins. A quick search in 
https://www.ncbi.nlm.nih.gov/pmc for “epigenetic 
toxins and human cancers” will yield thousands 
of articles about substances both natural and 
synthetic that can create such changes [112]. 
Not only are the epigenetic changes potential 
targets for treatment, but their inducers are as 
well [113,114]. The TME creates and supports 
epigenetic biochemical reactions that 
dynamically regulate DNA expression. 
Nucleotide methylation and histone modification 
induce the dysregulation of genes related to 
proliferation, apoptosis, and metastasis [115]. 
DNA methylation is strongly associated with the 
repression of transcription of tumor suppressor 
genes through adding a methyl group by DNA 
methyltransferases (DNMTs) [116]. Other 
reactions by histone deacetylases (HDACs) 
contribute to transcriptional repression by 

removing the acetyl group at lysine residues 
leading to tumorigenesis, as a result of the 
research, both biochemical pathways have 
become the focus of intense research to develop 
DNMT and HDAC inhibitors [117]. Histone 
acetyltransferases (HAT), erasers (histone 
demethylases (HDM) and histone methylases 
(HMT) have also become epigenetic targets of 
research [118]. Some drugs are currently 
available and used for their epigenetic effects 
such as Decitabine, which can prevent DNA re-
methylation and re-activate silenced suppressor 
genes [119]. Azacitidine is considered a global 
DNMT inhibitor and upon treatment of breast 
cancer cells, DNA re-methylation was inhibited 
for 23 out of 26 tested hypermethylated genes, 
allowing 5 tumor suppressor genes to be re-
expressed [120]. The problem with these and the 
many other drugs, thus far developed for their 
epigenetic effects, are the unintended 
consequences (side effects) on normal, healthy 
cells elsewhere in the body. Reducing and 
pulsing the doses given has helped somewhat to 
reduce the side effects while maintaining efficacy 
[121]. 
 
The tactics for targeting the TME have a certain 
amount of overlap with those that seek the 
destruction of the cancer stem cells because 
they are the major architects of their immediate 
environment. However, the chief goal of an anti-
metabolic cancer therapy is to disrupt the energy 
production pathways that support the cancer 
cells. For example, ENOX2 is a gene located on 
the long arm of the X chromosome and encodes 
for the Ecto-NOX protein. It is a member of the 
NOX family of NADPH oxidases which are 
important for energy production and the growth 
of the cell. Tumor-associated NADH oxidase 
(tNOX), has been identified as a target for low-
dose cell killing (apoptosis) of cancer cells by 
green tea catechins and Capsicum vanilloid 
combinations [122-125]. This protein is uniquely 
associated with all forms of cancer and is absent 
from normal cells and tissues. Another anti-
cancer metabolic strategy is to use the 
combination of two nutraceuticals: lipoic acid and 
calcium hydroxycitrate, which target two cancer 
energy enzymes ATP citrate lyase and pyruvate 
dehydrogenase kinase. Experimentally, this 
treatment was as efficient as chemotherapy in 
the mouse cancer models that were tested 
[126,127]. Clinically, in combination with low-
dose naltrexone, this anti-metabolic tactic has 
also been effective even against                     
advanced chemo-resistant carcinomas [128, 
129].  



 
 
 
 

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2.3 Genetic Molecular Targeting 
 
Targeting the abnormal genetics of cancer is the 
second anti-cancer strategy. Before we even 
begin to specifically target aberrant genetics, 
there are therapies that can be instituted for 
generally stabilizing genes which buys time for 
more definitive testing that allows for precise 
targeting of the cancer genome. Each of these 
agents has a multitude of beneficial effects, but 
chief among them is their ability to stabilize 
aberrant genetics, creating the time and 
opportunity for an integrative anticancer strategy. 
During the course of oncogenesis and tumor 
progression, cancer cells constitutively 
upregulate signaling pathways relevant to cell 
proliferation as a result of any number of genetic 
mutations. It is that genetic instability that leads 
to cancer cells acting as cancer in the first place, 
and it is those unstable mutations that account 
for the multiple cell lines that compose every 
tumor. Many agents have been identified that 
can aid in cell differentiation and reversion back 
to a phenotypically normal cell type [130]. Some 
of them are considered as follows.  
 
First on our list of genetic stabilizers is dimethyl 
sulfoxide. Dimethyl sulfoxide (DMSO) is an 
organosulfur compound with polar, aprotic, and 
amphiphilic properties. It serves as a solvent for 
many polar and nonpolar molecules and 
continues to be one of the most used solvents 
(vehicle) in medical applications and scientific 
research. It also displays a diversity of antitumor 
activities[131]. Previous studies have 
demonstrated that DMSO can modulate AP-1 
activity and lead to cell cycle arrest at the G1 
phase [132]. The fibrinolytic system, more 
appropriately referred to as the plasminogen 
activator (PA) system, controls not only the 
intravascular fibrin deposition (with its effects on 
cardio-vascular disease) but also participates in 
a wide variety of other physiologic and pathologic 
processes. In cancer, the components of this 
system are involved in tumor growth, invasion, 
and metastasis through their effect on 
angiogenesis and cell migration, by way of its 
effects on the extracellular matrix of the tumor 
microenvironment. Plasminogen activator 
components are found in most tumors and their 
expression signifies not only their function but 
also carries a prognostic value. Their expression 
is in turn modulated by cytokines and growth 
factors, many of which are up-regulated in 
cancer and found throughout the TME. DMSO 
can inhibit the activity of PA’s which helps to 
stabilize the TME and reduce the risk of 

metastasis [133]. Furthermore, DMSO can cause 
the maturation/differentiation, of at least some 
cancers, into a benign, more normal cell type 
[134,135]. 
 
Vitamin D is next on our list of genetic stabilizers. 
In addition to enhancing DNA repair, vitamin D 
also induces growth arrest and apoptosis of 
tumor cells and their nonneoplastic progenitors. 
Cell-based studies show that the active 
metabolite 1,25 dihydroxyvitamin D is the 
biologically active form that works through the 
vitamin D receptor to regulate gene transcription. 
Vitamin D (D3) is produced from 7-
dehydrocholesterol when skin is directly exposed 
to UVB light which, in more northern locations, is 
largely filtered out by the atmosphere. Vitamin D 
is readily sourced from various foods including 
fish, eggs, caviar (for the gourmets among us), 
some mushrooms, beef liver, and cheese. 
Regardless of whether vitamin D comes from the 
skin or the diet, vitamin D3 is transported through 
the blood by the vitamin D Binding Protein 
(DBP). Once delivered to the liver, vitamin D is 
hydroxylated on its side chain to form 25 
hydroxyvitamin D (25OH D). This is a stable 
metabolite whose serum levels are commonly 
used to assess vitamin D status. As needed and 
if available, D3 circulates to the kidneys which is 
the primary site where the active form of vitamin 
D, 1,25(OH)2 D, is produced through the 
genomic actions of 1α,25(OH)2 via the vitamin D 
receptor (VDR), and its analogs inhibit cell cycle 
progression and tumor cell growth. Mechanisms 
of action range from preventing cell proliferation 
(through cell cycle arrest) in cancer cells to 
inducing apoptosis, or suppressing cell adhesion 
molecules and growth factors that promote 
cellular homing and metastasis. It also affords 
important antioxidant protection and serves as an 
immunomodulatory for both the innate and 
adaptive arms of the immune system [136-140].  
 
Next comes indole-3-carbinol and its metabolite 
3,3′-diindolylmethane (DIM). They target multiple 
aspects of cancer cell cycle regulation and 
survival including Akt-NFκB signaling, caspase 
activation, and cyclin-dependent kinase activities. 
Furthermore, they stabilize estrogen metabolism, 
normalize estrogen receptor signaling, reduce 
endoplasmic reticulum stress, and limit BRCA 
gene expression. DNA hypermethylation is a 
common feature of cancer genetics. When 
methylation detox pathways start to fail, certain 
regions of the genome will accumulate too many 
methyl groups, such as at CpG promoter regions 
(segments of the DNA involved in DNA and RNA 



 
 
 
 

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transcription); this can lead to increased 
mutagenesis and eventual cancer development. 
Much research has demonstrated how DIM 
reduced methylation at 5 CpG promoter regions. 
For example, in split population studies, mice 
given Transgenic Adenocarcinoma of the Mouse 
Prostate (TRAMP) prostate cancer cells were 
also given DIM. The mice given the DIM showed 
a much lower incidence of cancer and metastasis 
than controls, as well as much higher expression 
of antioxidant/anticarcinogen protective enzymes 
NQO1 and NFR2 in prostate tissues [141-146].  
 
Curcumin, a component of turmeric (Curcuma 
longa), is a low molecular weight molecule that 
has antiproliferative activity and inhibits tumor 
initiation and propagation through a variety of 
pathways. It accomplishes this through several 
epigenetic effects that result in genetic 
modulation that then changes the expression of 
several key proteins, some of which are the 
cysteine-aspartic acid proteases (caspases). 
Caspases are a family of enzymes that play an 
essential role in apoptosis, necrosis, and 
inflammation. Research demonstrates that 
curcumin activates caspases-3 and -8 but not 
caspase-9, indicating that the apoptosis induced 
in cancer cells occurs via a membrane-mediated 
mechanism. Membrane-bound enzymes play 
other important roles in the perpetuation of 
cancer cells such as the ECTO-NOX 2 system. 
 
p53 (TP53) is a tumor suppressor gene and is 
responsible for protecting cells from tumorigenic 
alterations. Mutational inactivation of p53 is 
frequently observed in many cancers. Curcumin 
selectively increases p53 expression during the 
G2 phase of the cell cycle of carcinoma cells and 
releases cytochromes from the mitochondria, 
which is an essential requirement for then 
inducing p53-dependent apoptosis in the cancer 
cell. 
 
Another protein affected by curcumin is Akt 
(protein kinase B), a serine/threonine kinase. It is 
a critical enzyme in signal transduction pathways 
involved in cell proliferation, apoptosis, and 
angiogenesis. Curcumin inhibited the 
phosphorylation of Akt in a dose-dependent 
manner leading to another pathway of apoptosis. 
 
Curcumin also induces the upregulation of 
carcinogen-detoxifying enzymes, such as 
glutathione S-transferases, which have 
antioxidation effects and suppresses 
cyclooxygenase that in turn lead to the reduction 
of the level of inflammation and the stimulation of 

cancer stem cells. Real-time animal model 
studies have demonstrated that curcumin also 
decreased the expression of DNA damage 
response genes, including serine/threonine 
kinase (ATM), ataxia telangiectasia and Rad3-
related protein (ATR), breast cancer 1 (BRCA1), 
14-3-3σ,  DNA-dependent protein kinase (DNA-
PK), and O6-methylguanine-DNA 
methyltransferase (MGMT); thus, the reduction of 
a DNA damage response is but a part of the 
reason for curcumin-induced growth inhibition of 
cancer cells [147-149]. 
 
Sulforaphane (SFN) is an isothiocyanate found in 
cruciferous vegetables such as broccoli, brussel 
sprouts, cauliflower, and cabbage. 
Experimentally, in cell cultures and animal 
models, SFN was shown to be a highly effective 
chemoprotective against carcinogen-induced, 
and genetic animal cancer models, as well as in 
xenograft transplant models of cancer. The early 
research focused on the detoxification ability of 
SFN to induce phase 2 enzyme pathways. Later 
studies showed that SFN could cause cancer 
cells to enter G2/M phase arrest and result in 
apoptotic cell death, with the latter being 
evidenced by caspase-mediated cleavage of 
poly(ADP-ribose) polymerase and increased 
release of histone-associated DNA fragments 
from the tumor downstream. Furthermore, it 
leads to the transcriptional activation of genes 
including tumor suppressor genes. The effect on 
cancer genetics is profound and therapeutically 
beneficial [150-153]. 
 
Fish oil rounds out our list of top genetic 
stabilizing supplements. One of many changes 
that occur to the cancer cell’s biochemistry and 
genetics is in the production, metabolism, and 
expression of microRNAs (miRNAs). First 
discovered in the early 1990s, their importance 
as a distinct class of biological regulators was not 
appreciated for another decade. MicroRNAs 
(miRNAs) are short molecules, just 21–25 
nucleotides long, but can have powerful effects 
on gene expression. More than 2000 miRNAs 
have been identified including many specific 
miRNAs that have been found to be associated 
with cancer and the risk of metastasis. The 
identification of circulating miRNA specific to 
metastatic cancer presents a unique opportunity 
for early disease identification and for monitoring 
disease burden as a circulating biomarker. For 
example, abnormal activation of some miRNAs 
found in the blood, let-151a, miR-21, miR-155, 
miR-,145 miR-18a, and miR-16, as well as 
tissue-specific miRNAs, miR-182, miR-145, miR-



 
 
 
 

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21, miR-155/154, miR-203, miR-213, and miR-7, 
are often found in patients affected by breast 
cancer. Furthermore, there is a growing body of 
evidence on the value of miRNAs associated 
with the development of drug resistance, 
suggesting their values, once targeted, as a 
potential approach to overcoming 
chemoresistance. miRNAs that are absorbed into 
our bloodstream from genetically modified 
organism (GMO) foods are currently being 
studied for their oncogenic potential, as they are 
normally foreign to human biology. Fish oil can 
modulate the expression of the miRNAs which 
can significantly reduce the risk of metastasis 
while having many other anticancer effects [154-
159]. 
 
The science of genetics studies the genes that 
make up our chromosomes, which lead to 
inherited characteristics; think Gregor Mendle 
and his peas. Genomics is the study of large 
groups of genes or even the entire genome, 
looking for mutations, fusions, deletions, loss of 
heterozygosity, etc. variations and alterations 
that lead to the expression of cancer. Aberrations 
of the genome lead to the transcription of the 
faulty gene into a messenger RNA (mRNA) 
molecule, that leaves the cell nucleus and enters 
the cytoplasm, where it directs the synthesis of 
the protein for which it encodes. Abnormal genes 
lead to abnormal proteins. The study of proteins 
is called proteomics; it’s primarily the functional 
proteins, which includes enzyme activities, as 
well as protein/protein interactions (such as 
immune receptor sites) and post-translational 
modifications of the proteins that are of the most 
interest because they are the most antigenic and 
hence the most targetable/treatable. The 
sciences of genomics and proteomics have 
opened the door to what is being referred to as 
“precision medicine” [160]. Precision medicine is 
"an emerging approach for disease treatment 
and prevention that takes into account individual 
variability in genes, environment, and lifestyle for 
each person". This personalized approach allows 
clinicians to predict more accurately which 
treatment is more likely to work for which person 
[161]. This is in contrast to a one-size-fits-all 
approach, in which cancer treatment strategies 
are developed for the average person based 
upon group clinical trials (cohorts), with little 
consideration for the differences between 
individuals. 
 
Precision medicine works by profiling live or 
preserved cells for biomarkers that indicate an 
abnormal process, gene or protein is present that 

is carcinogenic and/or cancer-promoting [162]. 
Cancer inhibiting genes that have been 
abnormally silenced are also tested for. Cutting 
edge technologies that can detect these clinically 
useful aberrations include: Next-Generation 
Sequencing (which allows for whole-exome DNA 
sequencing and whole transcriptome RNA 
sequencing), DNA Sequencing (sequence 
analysis reliably detects DNA mutations, copy 
number variations, and gene fusions across the 
entire exome), RNA Sequencing (is done to 
detect clinically relevant aberrations, in particular, 
gene-fusion events and splice variants), 
Immunohistochemistry biomarkers, in situ 
hybridization (to detect amplification and fusion 
events), and methylation analysis. When 
evaluated as a group, disease-specific lab test 
panels are developed which can then zero in on 
the aberrations for any individual patient to 
improve the therapeutic response [163-         
165]. 
 
Based upon the biomarkers found, clinically 
beneficial therapies may be employed including 
the use of; hormone therapies, signal 
transduction inhibitors, gene expression 
modulators, apoptosis inducers, angiogenesis 
inhibitors, immunotherapies, and toxin delivery 
molecules [166,167]. Some of the commonly 
used small molecules include the “nibs” ( 
tyrosine-kinase and serine/threonine kinase 
inhibitors) and the “mabs” (monoclonal 
antibodies). Monoclonal antibodies have been 
developed to attack growth receptors of the 
cancer cells, growth factors for new blood 
vessels that feed the tumor, and targets on cells 
of the immune system to dis-inhibit their activity 
[168]. Natural substances too can be used to 
target specific aberrations; a few, of many, 
examples [169,170]: 
 

p53, p73 Aronia melanocarpa [171,172] 
VEGF Omega-3 Fatty Acids [173] 
JAK/STAT-
3 

Astaxanthin [174,175] 

PI3K/AKT Viscum alb [176] 
KDR Artemisinin [177] 
MMP2, 
MMP9 

Curcumin [178] 

HER2-neu Quercetin [179] 
EGFR Silymarin [180] 
VE-cadherin Camellia sinensis [181] 
HIF-1α Ginseng [182] 
NF-κB Liquorice [183] 
BCL2 Scutellaria baicalensis[184] 
KRAS Coffee [185] 
Mcl-1 Piperlongumine [186] 



 
 
 
 

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2.4 Immunotherapy 
 
Immuno-therapy is the third anti-cancer strategy. 
Edward Jenner was a pioneering English 
physician and scientist who improved the 
procedure of smallpox inoculation to create the 
smallpox vaccine in 1796 [187,188]. In the 
scientific fashion, he purposely exposed people 
that he had vaccinated against smallpox to prove 
that the cowpox pus that he used did indeed 
confer protective resistance. Although others 
before him had used cowpox to provide 
protection from smallpox, he was the first to then 
demonstrate that it did in fact work and that the 
effect was reproducible in subsequent patients 
[189-191]. Although not understanding the 
intricacies of the immune system, because he 
applied the scientific method, as it existed in his 
time, he is referred to as the “Father of 
Immunology” [192]. 
 
Since Jenner’s time, imuno-therapy has evolved 
into an office-based strategy for which they write 
very thick books and, in the broadest terms 
possible, it is a treatment that uses the immune 
system, in some way, to identify, attack, and 
destroy the cancer. Using the immune system 
against cancer can be accomplished through 
active or passive pathways. As a quick overview, 
there are over one hundred and eighty-seven cell 
types identified within the immune system. It 
includes the lymphatic system along with the 
bone marrow, spleen, thymus, and, of course, 
lymph nodes. Cells known as CD4 T cells are the 
“apparent brains” of the immune system and they 
coordinate the central immune response to any 
serious health threat. 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 cells respond to viruses and cancer. 
Suppressor T cells are used to downregulate the 
actions of the immune system after the threat 
has been eliminated through negative feedback. 
Macrophages are voracious amoeboid-like 
lymphocytes that eat foreign substances and 
send a message back to the rest of the immune 
system indicating what further immune response 
is necessary. Macrophages and their cousins, 
the dendritic cells, are involved in all aspects of 
the immune response by initially sending out the 
alarm that something is amiss. Natural Killer cells 
are preprogrammed at their birth to destroy 
virally infected cells, cancer cells, some bacteria, 
and parasites on contact without the need for 
further direction from the CD4 cells. Some 
mushroom extracts and the bioengineered 

nutraceutical AiE10
TM

 can increase the 
concentration and activity of natural killer cells. 
 
The immune response cascade operates 
according to three directives. The first is to 
recognize that which is foreign and sound the 
alarm soon enough to thwart the invader. 
Molecules and cell surfaces that are identified as 
foreign are referred to as antigens and have the 
ability to elicit an immunogenic response. The 
second directive is to respond to the alarm with 
enough of a counterattack to effectively 
neutralize the invader quickly. The third directive 
is to remember what happened so that if the 
same situation were to arise again, an effective 
response could be generated faster. The length 
and efficacy of the immune response depends 
upon the “intactness” of the underlying 
biochemistry. The immune response cascade is 
the ultimate biological information processing 
and transfer vehicle designed to define, defend, 
and integrate oneself relative to the environment 
that surrounds us. When there is a 
miscommunication, disease ensues due to 
corruption, misdirection, or a lack of that 
informational flow.  
 
Active immune therapies include, among other 
agents, IL-2, IFN-g, and IFN-a cytokines to 
stimulate the TH1 cells, pathways, and natural 
killer cells. Monoclonal antibodies, checkpoint 
inhibitors, that disinhibit an immune response are 
also an active immunotherapy that seems to be 
most effective when some support has been 
given to the immune system first. Other active 
therapies include creating primed dendritic cells 
(for example, Sipuleucel-T (Provenge)) and 
natural killer cells and then infusing them into the 
patient to “patch” holes and reconstitute an 
effective anticancer response. 
 
Passive immunotherapies include the use of 
infused antibodies to bind to cancer cells. Then, 
when natural killer cells encounter antibody-
coated cells, the latter’s Fc regions interact with 
their Fc receptors, releasing perforin and 
granzyme B to kill the tumor cell. Adoptive T cell 
therapy is another passive immunotherapy. 
Several ways of producing and obtaining tumor-
targeted T cells have been developed. T cell 
Infiltrating Lymphocytes (TILs), specific to the 
tumor antigens, can be removed from a tumor 
sample with a core biopsy and then purified with 
a cell separator or filtered from the blood. 
Subsequent activation with cytokines and cell 
culturing is performed ex vivo, and then the 
results were reinfused into the patient. Activation 



 
 
 
 

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can take place through gene therapy or by 
exposing the T cells to tumor antigens in the 
presence of cytokines. TILs can also be 
stimulated in vivo with hypofractionated SBRT to 
induce an abscopal effect, which when achieved 
can have miraculous results. According to the 
National Cancer Institute, the abscopal effect 
“describes the shrinking or disappearance of 
tumors in parts of the body that were not the 
direct target of local therapy” [193]. It was first 
described in 1953, by a researcher named R. H. 
Mole who demonstrated that radiation could 
shrink a tumor on one side of a mouse and lead 
to the regression of an untreated tumor on the 
other side of the animal[194]. He coined the term 
“abscopal effect” from the Latin ab (position away 
from) and scopus (mark or target). Since the 
phenomena was first observed using radiation, it 
was assumed that that was the key to the 
response. A lot of research has been done on 
varying different parameters of the radiation in 
order to reliably reproduce the effect [195]. 
Tumor-infiltrating lymphocytes are seen as an 
important part of the “recipe” as they can signal 
and initiate a counter-tumor cascade and bode 
well prognostically [196]. Further research has 
demonstrated that cryotherapy, too, can trigger 
an abscopal response [197]. In my experience, it 
seems that any locally applied treatment that 
causes the sudden death of a large number of 
cancer cells, thus quickly releasing antigens, 
without suppressing normal systemic physiology 
(i.e. the immune system), can trigger a cascade 
of events that can lead to the death of tumors far 
removed from the point of the therapy. This 
includes; radio frequency ablation (RFA), 
hyperthermia, hi frequency ultrasound (HiFu), 
cryotherapy, and of course fractional dose 
radiation therapy [198-204]. 
 
Combining these “mildly” oncolytic therapies with 
checkpoint inhibitors has yielded better results 
[205,206]. The checkpoint inhibitors are helpful 
only to the point that the immune system is still 
basically structurally intact and functionally 
effective. When the principles of immune 
reconstitution are followed, the therapeutic 
response can be much more beneficial [207]. 
 
A “new”, state-of-the-art, passive immunotherapy 
is the use of chimeric antigen receptors (CARs, 
also known as chimeric immunoreceptors, 
chimeric T cell receptors, or artificial T cell 
receptors) which are bioengineered cell 
receptors that combine a new specificity with an 
immune cell to target cancer cells. Essentially, 
what is done is that specific monoclonal antibody 

fractions are grafted onto T cell receptors. The 
receptors are referred to as chimeric because 
they are a fusion of proteins and receptors from 
different immune sources. CAR-T cell therapy 
refers to an infusion of such specifically 
transformed cells for targeted cancer therapy. 
CAR-T cells destroy the cancer cells through 
several mechanisms such as having a direct 
cytotoxic effect and/or stimulating other cells of 
the immune system through the release of 
various cytokines and growth factors. Due to the 
CAR-T cells very narrow specificity, less 
prominent tumor cell lines can be missed 
allowing for a future recurrence [208-218]. 
 
Overall, immunotherapy is designed to correct, 
stimulate, direct, or reconstitute an effective 
anticancer response. Immune reconstitution is 
the evolving clinical science of restoring immune 
competence by correcting biochemical 
imbalances, augmenting cytokines, restoring 
cascade pathways, and/or implanting specific 
stem cells to bridge areas of damage. All severe 
or chronic diseases are known to have one or 
more significant defects in the immune system 
adversely affecting the immunological 
imperatives of recognition, response, and 
memory which, in the case of cancer, leads to 
anergy and tolerance. Testing for and breaking 
anergy is the first step in immune reconstitution 
[219]. Correcting anergy is of critical importance 
because it directly correlates to the stage of 
cancer: over 90% of patients with Stage 4 
disease are found to be anergic [220]. The 
immune system cannot fight something that it 
doesn’t know is there, and that’s exactly what 
arises with anergy. Anergy manifests when there 
is a failure of signal transmission at ANY point in 
the immune response cascade. Before we can 
break anergy, and wake up the immune system, 
we must make sure that we are dealing with true 
anergy as opposed to another pathology.  
 
Of historical interest, some years ago the 
Mérieux Company manufactured a skin test 
called the “Multitest Mérieux” or “CMI Multitest” 
system (Istituto Merieux Italia, Rome, Italy). It is 
used as a general test for the level of the cellular 
immune response. It is an intradermal test of skin 
reactivity (similar to allergy tests) in which a 
control (glycerol) is used with seven common 
antigens of bacterial or fungal origin (tetanus 
toxoid, tuberculin, diphtheria, streptococcus, 
candida, trichophyton, and proteus). In this test, 
reactions are categorized according to the 
number of antigens provoking a response, and 
the summed magnitude of the skin response to 



 
 
 
 

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all seven antigens. Based on the chart and 
information supplied with the simple skin test, 
basic anergy can be quickly assessed and 
quantified [221]. Unfortunately, this test cannot 
tell us where in the recognition/response chain of 
events the problem lies. However, specialized 
blood tests are now generally able to do that. 
Once this state of unresponsiveness has been 
confirmed, the next step in breaking anergy is 
with an immunotherapy protocol specific to the 
area(s) of immune response dysfunction as 
briefly described above.  
 

2.5 Cancer Stem Cells 
 
As a short overview, cancer stem cells (CSCs) 
are cancer cells (found within tumors or 
hematological cancers) that possess 
characteristics associated with normal stem cells, 
specifically the ability to give rise to all of the 
heterogeneous cancer cell lines found in a 
particular tumor. Targeting them is the fourth 
anti-cancer strategy. Until recently, attacking 
them would have been included in the general 
biochemical targeting strategy but recent 
research has shown them to be a separate and 
viable strategy. CSCs mediate tumor initiation, 
progression, and metastasis, and inhibiting them 
is an emerging new area of research to prevent, 
stop, and reverse tumor growth. They play key 
roles in tumor metastasis, drug resistance, and 
cancer relapse. Oncologic research has 
established that subpopulations of cells, 
identified by monoclonal antibodies to specific 
cell surface markers, behaved like 
developmental stem cells in their capacity to 
regrow the human tumors, for multiple 
generations, in experimental immune-deficient 
animal hosts. In all of the cancers studied so far, 
there is good evidence that CSCs are relatively 
resistant to radiation therapy and chemotherapy 
because of their slow rate of growth, indicating 
that novel CSC-targeted therapies are needed. 
Several pathways are promising targets against 
CSCs including inducing their apoptosis, 
inhibiting stem cell self-renewal to either stop 
their division or to promote their differentiation, or 
targeting the CSC milieu in the TME that 
supports them. The anti-CSC agents are 
categorized under two broad headings: small- 
and macromolecules with different subclasses 
such as kinase inhibitors and polypeptides. One 
of the first and safest agents to be recognized as 
a CSC inhibitor is Metformin [222-235].  
 
Tumor initiation can either be driven by 
transformed differentiated cells or transformed 

tissue-resident stem cells forming the new 
cancer stem cells [236,237]. As tissue stem cells 
already possess unlimited growth potential, it is 
believed that the transformation into a CSC 
requires only a very small number of genomic 
changes

 
 [238]. Multiple biomarkers that 

characterize CSCs have been identified and 
correlated to diagnosis, therapy, and prognosis 
[239]. They have been shown to display a high 
degree of plasticity, which changes their 
phenotypic and functional appearance making it 
harder to track them and predict their activity. 
Such shifts in their expression can be induced by 
chemo- and radiation therapy as well as by 
senescent tumor cells. Therapeutic regimens 
such as chemo- or radiation therapy shift the 
composition of tumor cell subpopulations 
changes by first killing some of the tumor cells, 
those with the highest proliferative capacity, 
causing a decrease in tumor size, while CSCs 
which multiply at a much slower rate survive. 
Instead of dying, some of the tumor cells will 
become senescent which causes further 
alterations in the tumor microenvironment that 
better support the CSCs [240]. 
 
The transformation to a cancer stem cell can 
take place during tissue regeneration or can be 
initiated and/or accelerated as a response to 
infections, toxins, radiation, or metabolic 
epigenetic influences that cause mutations [241]. 
During the process of transformation, oncogenes 
are overexpressed and tumor suppressor genes 
are inactivated, hence promoting the creation of, 
and uncontrolled growth of the CSCs. As a 
consequence of the transformative process, the 
affected cells “de-differentiate” and acquire stem 
cell self-renewal characteristics forming the 
nucleus of the cancer [242,243]. The mutations 
of the CSC progeny have a higher rate of 
replication which leads to the formation of a 
tumor [244].  
 
Anti-CSC research has yielded some very 
promising therapeutic approaches. 
Nutraceuticals derived from herb and vegetable 
extracts show anti-CSC activity at various levels 
of clinical utility. Cruciferous vegetables belong to 
the Cruciferae family such as arugula, bok choy, 
broccoli, broccoli rabe, brussel sprouts, cabbage, 
and others, contain anti-cancer isothiocyanates 
including sulforaphane, that are enzymatically 
hydrolyzed from glucosinolates [245]. Normal 
dietary “doses” of isothiocyanate sulforaphane 
have been shown to have anti-CSC activity by 
altering phosphorylation of several kinases and 
their substrates including  Glycogen synthase 



 
 
 
 

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kinase 3 (GSK3), Jun N-terminal Kinase (JNK), 
and Protein Kinase C (PKC) [246]. Soy 
isoflavones like genistein have been shown to 
have a potent anti-CSC effect by inhibiting the 
phosphorylation of Protein kinase B (AKT) and 
Forkhead Box O 3a (FOXO3a) [247]. 
Polyphenolic catechins including 
epigallocatechin-3-gallate (EGCG) found in 
green tea extracts have demonstrated anti-CSC 
activity, against a variety of cancers, through its 
ability to inhibit NF-κB activity, Mitogen-Activated 
Protein Kinase (MAPK) pathway, activator 
protein-1 (AP1) activity, and EGFR-mediated 
downstream signaling pathways [248,249]. Other 
anti-CSC nutraceuticals are derived from 
quercetin, curcumin, resveratrol, and ginger 
[250]. More potent anti-CSC pharmaceuticals are 
also derived from plant sources. Taxol is derived 
from the bark of the Pacific yew tree (Taxus 
brevifolia) and was discovered, through a 
random screening of approximately 15,000 
species of plants, to have powerful anti-CSC 
activity against many different cancers [251]. 
Vinca alkaloids are a group of drugs that were 
originally extracted from the Madagascar 
periwinkle plant, Catharanthus roseus G. Don, 
and have anti-CSC activity as well as cytotoxic 
effects. There are three major vinca alkaloids in 
clinical use: Vinblastine (VBL), vinorelbine (VRL), 
and vincristine (VCR) [252]. 
 
Several pharmaceuticals have been “re-
purposed” as anti-cancer agents when their anti-
CSC “side-effect” was noticed. Studies have 
demonstrated that Metformins’ anti-cancer, anti-
CSC effects go far beyond its ability to lower 
blood sugar in that Metformin impairs cellular 
metabolism and suppresses oncogenic signaling 
pathways, including tyrosine kinase receptors, 
PI3K/Akt, and mTOR pathways [253]. 
Furthermore, it suppressed the self-renewal 
ability of cancer stem cells and induced G0/G1 
phase arrest by blocking the activity of cyclin-
dependent kinases. In studies on osteosarcoma 
cancer cells Metformin-induced apoptosis 
through a mitochondria-dependent pathway, 
leading to the collapse of the mitochondrial 
transmembrane potential and the production of 
oxidatively destructive reactive oxygen species 
[254]. This destruction of the already 
compromised mitochondria further decreased 
ATP synthesis and triggered autophagy cancer 
cell death [255]. Thus, Metformin is an excellent 
addition to a metabolic strategy in that its activity 
is synergistic with the goals of further degrading 
the already damaged mitochondria in CSCs and 
cancer cells [256]. When combined with a beta-

blocker and aspirin the anti-CSC and anti-
metastasis effects are even more pronounced 
[257,258]. 
 
Doxycycline too has been “re-purposed” for the 
fight against cancer. One of the FDA recognized 
side effects of doxycycline is the inhibition of 
mitochondrial biogenesis. Currently, in                       
the https://www.anticancerfund.org/en/redo-db 
database, there is a listing of 356 “non-cancer 
drugs” which have shown some evidence of 
anticancer activity. Amongst them, doxycycline is 
high on the list of beneficial activity [259]. Sorting 
them out into a generally useful algorithm is a 
research project for WATSON, but for now, we 
have some important clues. 
 
Doxycycline is a known inhibitor of the small 
mitochondrial ribosome (28S) and, as a 
consequence, is an inhibitor of mitochondrial 
protein translation necessary for biogenesis 
[260]. In vitro and in vivo evidence demonstrates 
the inhibitory effects of Doxycycline on cancer 
growth through mitochondrial destruction and the 
consequence of CSC suppression [261]. 
Azithromycin inhibits the large mitochondrial 
ribosome (39S) and enhanced the tumor 
necrosis factor-related apoptosis-inducing ligand 
(TRAIL) activity, which selectively targets tumor 
cells without damaging healthy cells as an off-
target “side-effect” [262]. Together, these two 
antibiotics have a synergistic, anti-metabolic 
effect on CSCs that is greater than either one 
alone. We can add to the targeted anti-metabolic 
CSC effect with vitamin C that, in high dose IV’s 
(greater than 15 grams), acts as a pro-oxidant, 
which can produce free radicals further stressing 
the already dysfunctional mitochondria and 
hastening their destruction [263]. This 
combination of antibiotics and vitamin C has 
shown efficacy both in vitro and in vivo [264]. 
Further compromising the CSCs mitochondria 
leading to their destruction, seems to be an 
important process for stopping cancer. A shift 
from respiration to fermentation (glucose 
pathway) is not the only energy production shift 
that cancer cells, and in particular that CSCs can 
use, but it does seem to be an important and 
common one. To an extent, CSCs are 
metabolically flexible so multiple pathways may 
need to be blocked, often simultaneously, to 
minimize the risk of selective metabolic escape. 
In addition to inhibiting the major glucose 
pathway, as described above, fatty acids and 
glutamine can also be used by many CSCs to 
support their deranged metabolism. Lipophilic 
statins can inhibit the use of fatty acids as an 



 
 
 
 

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energy source for many types of cancer [265]. 
Hydroxychloroquine blocks cancer cells' ability to 
scavenge nutrients, including glutamine, through 
macropinocytosis, thereby closing yet another 
pathway for energy generation by the mutated 
cells [266]. Research on new anti-CSC strategies 
focuses on their signaling pathways and cellular 
communication system including; Hedgehog, 
Wnt/beta-catenin, Notch, Toll-like receptor 4 
(TLR-4), Toll-like receptor 9 (TLR-9), Integrins, 
EGFR, IL-1, IL-6, Peroxisome proliferator-
activated receptor (PPAR), and others. 
 
CSCs and tumor cells, like all eukaryotic cells, 
produce structures called exosomes in their 
endosomal compartment [267]. They are 
approximately 100 nm in diameter and are 
surrounded by a lipid bilayer membrane. 
Exosomes have been recognized as potent 
vehicles of intercellular communication due to 
their capacity to transfer proteins, lipids, and 
nucleic acids; thereby influencing various 
physiological and pathological functions of both 
recipient and parent cells [268]. The involvement 
of exosomes in the phenotype transformation 
from non-CSC to CSC has been recently 
evidenced by research on the X chromosome 
long non-coding RNA, which is overexpressed in 
malignant tumor tissues and activates Toll-like 
receptor (TLR) 7 and NF-κB inflammatory 
signaling [269]. 
 
Exosomes have been reported to interact with 
the cells of the immune system, modulating and 
downregulating its response thus allowing for 
tumor progression [270]. Tumor-derived 
exosomes (TEXs) induce apoptosis of the 
activated CD8+ (cluster of differentiation 8) T 
cells (which have an anti-cancer surveillance 
function), suppress natural killer (NK) cell activity, 
promote the induction of regulatory T cells 
(Tregs) and myeloid-derived suppressor cells, 
and interfere with monocyte differentiation into 
anti-cancer dendritic cells [271]. While TEXs form 
the immunosuppressive microenvironment, Treg-
derived exosomes inhibit the induction of 
cytotoxic T lymphocytes, further allowing for the 
growth and spread of the tumor [272]. As a result 
of the research on tumor cell exosomes, they 
have become a promising target for the 
treatment of cancer but as of yet this therapy is 
not available [273-276]. 
 

2.6 Cytotoxic Cancer Therapy 
 
Cytotoxic cancer treatments are traditionally 
covered by the term chemotherapy and have 

come to imply the use of agents that act, 
separately from the body at large, as intracellular 
poisons to inhibit mitosis or directly induce some 
sort of cell death and is the fifth anti-cancer 
strategy. Substances that accomplish this as a 
secondary effect through blocking extracellular 
signals or which act through a specific genetic, 
enzymatic, or hormonal pathway are excluded 
from this therapeutic strategy as they are 
referred to as targeted therapies and elsewhere 
described. Chemotherapeutic agents are 
characteristically purified to the point of being a 
chemical, and may be of natural origin or 
synthetically created. The deliberate use of 
natural, herbal source agents began in the early 
1920s, including Viscum alkaloids and lectins, 
and they are still used today, whereas the first 
synthetic agent, nitrogen mustard, was 
“discovered accidentally” during World War II 
when it was observed that it could shrink 
lymphoma tumors in mice. A few years later, it 
was discovered that alkaloids extracted from the 
Vinca rosea plant were useful in treating 
Hodgkin’s disease, and so a multibillion dollar 
industry was birthed creating and extracting new 
substances helpful in the “war on cancer”. 
Unfortunately, many of these substances have 
similar effects on healthy cells, thus creating a 
multitude of side effects and limiting their 
usefulness. Newer protocols that use lower 
doses of these agents, such as metronomic or 
insulin potentiated chemotherapy, are showing 
good results with far fewer side effects. 
Metronomic, low dose chemotherapy has been in 
development for two decades and seems to act 
through several mechanisms including inhibiting 
the growth of new blood vessels, the restoration 
of an anticancer immune response, and the 
induction of tumor dormancy. Whereas Insulin 
Potentiated Therapy (IPT), another low dose 
strategy, takes physiologic advantage of the 
excessive number of insulin receptors found on 
the cell surface of cancer cells. Giving insulin just 
prior to the infusion of low dose 
chemotherapeutic agents, usually in a 
combination designed to intervene at several 
sites of the cell cycle, causes much fewer side 
effects and can hold the cancer at bay, while 
buying time to reconstitute an effective immune 
response or integrate another anti-cancer 
therapeutic strategy. IPT has been in 
development and clinical use since the 1930s 
and has been used to help treat other chronic 
diseases as well 

 
[277-290]. 

 
Cytotoxic chemotherapy is usually administered 
as per a protocol derived by treating a group of 



 
 
 
 

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15 

 

people (cohorts) with a similar diagnosis. These 
clinical trials are done to determine the general 
dose and combination of agents that are most 
effective and least toxic according to the 
structure of the trial for that disease diagnosis. 
This approach is designed to attack different 
genetic targets and the aspects of DNA 
transcription of rapidly dividing cells [291-293]. A 
more contemporary way for using cytotoxic 
agents is to target them so that the agents affect 
biochemical factors or cellular pathways that are 
unique to the malignant cells or characteristic of 
tumors based upon genetic studies.  
 

Cytotoxic chemotherapy can be very good at 
killing rapidly dividing cells, such as those found 
in a growing tumor, but are not good at killing the 
slow-growing cancer stem cells that are at the 
root of the problem. This leads to the observed 
high risk for recurrence and to eventual multi-
drug resistance [294]. There is a great deal of 
research currently engaged in addressing this 
problem and certain drug combinations have 
been found that can lessen this issue by making 
the cytotoxic response more effective [295]. At 
this point, we know that P-glycoprotein (also 
known as multidrug resistance protein 1 (MDR1) 
or ATP-binding cassette sub-family B member 1 
(ABCB1)) plays a crucial role in determining the 
neutralizing response against chemotherapy. P-
glycoprotein (p-gp) acts as an ATP-dependent 
pump that pumps out small molecules from cells, 
including chemotherapeutic agents, before they 
can exert their cytotoxic effects. Research 
demonstrates that p-glycoprotein expression 
levels correlate inversely with drug efficacy, 
which suggests the rationale for developing p-
glycoprotein inhibitors for treatment against 
cancer [296]. While new agents are being 
developed and going through drug trials, some 
currently available pharmaceuticals are helpful 
against multi-drug resistance. Verapamil is an L-
type calcium channel blocker with antiarrhythmic, 
antianginal, and antihypertensive activity, but is 
also a p-gp inhibitor. Unfortunately, the dose 
required to achieve this effect can cause 
significant hypotension thus limiting its 
usefulness [297]. Other agents that may be 
helpful are to be found within the class of drugs 
known as proton pump inhibitors (PPIs) [298].  
 

Proton pump inhibitors (PPIs) given before the 
chemotherapy have been shown to inhibit mRNA 
levels of vacuolar-type ATPase (V-ATPases),  
multidrug resistance mutation 1 (MDR1), 
multidrug resistance protein 1 (MRP1), 
phosphatidylinositol 3-kinases (PI3K), Akt, 
mTOR, and HIF-1α. PPIs inhibited V-ATPases 

and down-regulated the expressions of P-gp and 
MRP1 in a dose-dependent manner both in vitro 
and in vivo [299]. 
 
There are also low concentration natural agents 
that are cytotoxic to cancer cells that may be 
used with low doses of cytotoxic chemotherapy 
to reduce side effects and improve the quality of 
life. In use for a 100 years, research has shown 
that Viscum album (mistletoe) extracts (VAE) 
have a significant positive impact on the quality 
of life and the reduction of the side effects from 
conventional therapies (chemotherapy, radiation) 
in experimental trials as well as in routine daily 
application [300,301]. Furthermore, pooled data 
from multiple clinical studies demonstrate that 
adjuvant treatment of cancer patients with the 
VAE is associated with better overall survival 
[302]. In some cases not only is VAE effective as 
an additional cytotoxic, anti-cancer agent, but it 
may succeed when more conventional 
chemotherapy and immunotherapy have failed 
[303-310]. 
 
Another important benefit of VAE is its ability to 
overcome some scenarios of chemoresistance. 
Axl protein is a receptor for tyrosine kinases. 
Some reports showed that targeting anexelekto 
(Axl) enhanced EGFR TKI response in selected 
EGFR wild type (WT) NSCLC patients. Studies 
have found that when targeting Axl in EGFR WT 
NSCLC cells, the cells showed a more sensitive 
response to erlotinib than those that 
overexpressed Axl thereby overcoming 
chemoresistance [311,312]. 
 
Chemoresistance is a big problem with 
chemotherapy as the agents seem to have an 
almost evolutionary effect on tumors, selecting 
for the most sensitive cancer cells and leaving 
the rest, including the CSCs untouched, or more 
mutated, therein setting the stage for a 
recurrence. Radiation therapy has similar 
drawbacks. Doxycycline is helpful with both 
treatment modalities to reduce chemoresistance, 
largely through interrupting oxidative 
phosphorylation by inhibiting moieties of the 
electron transport chain [313,314]. This brings us 
back to the necessity for targeting CSCs to help 
overcome chemoresistance [315-319]. 
 
Another cytotoxic strategy that generates much 
less chemoresistance because it also targets 
CSCs is the use of vitamin C (VC) and vitamin 
K(3) (VK(3). administered intravenously in a 
VC:VK(3) ratio of 100:1 exhibit synergistic 
antitumor activity and preferentially kills tumor 



 
 
 
 

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16 

 

cells without harming normal cells [320]. This 
natural vitamin combination accomplishes this 
through a process of autoschizis, a novel type of 
necrosis characterized by exaggerated 
membrane damage and progressive loss of 
organelle-free cytoplasm through a series of self-
excisions [321]. This combination also attacks 
the DNA of cancer cells since a deficiency of 
alkaline and acid DNase is a hallmark in all living 
cancer cells and they are reactivated in the early 
stages of cancer cell death by vitamin C (acid 
DNase) and vitamin K(3) (alkaline DNase) 
leading to DNA fragmentation [322]. Vitamin C by 
itself can regulate the proliferation and 
differentiation of cancer stem cells, the amount 
and stability of collagen, extracellular matrix 
remodeling, anti-cancer immunity, and hypoxia in 
the tumor microenvironment, hence 
epigenetically suppressing the CSCs and 
downregulating chemoresistance [323-326]. 
When combined with doxycycline, the effect is 
even more pronounced [327,328]. 
 

2.7 Supportive Tactics 
 

There are other therapeutic tactics that may be 
synergistic, but they are not considered 
strategies unto themselves because their anti-
cancer effects are less reliable. This includes 
energy-based therapies such as homeopathy 
and acupuncture, and psychodynamic tactics like 
psychoneuroimmunology, visualization, prayer, 
and meditation practices. Other tactics employ 
the use of oncolytic viruses, oxidative therapies 
(ozone), Traditional Chinese Medicine, 
Naturopathy, Ayurvedic herbal medicines, and 
detoxification protocols, to name but a few. There 
is no doubt that some of them can be 
extraordinarily beneficial to the patient by 
reducing physical symptoms, psychological 
stress and by engendering a feeling of more self-
control against a disease that threatens total 
chaos. Indeed hundreds of books and articles 
have been scribed as to their use and 
intermittent efficacy by notable physicians and 
practitioners; to this day the well-documented 
phenomena of the spontaneous remission of 
cancer remains a medical mystery. Early in my 
career, the immunotherapeutic strategy that I 
employed against cancer was still considered 
something just short of quackery, and the clinical 
responses to it were often attributed to this 
phenomenon. 
 

3. DISCUSSION 
 

An evidence-based medical practice is 
established through the application and 

integration of the best clinical research available 
at the time, balanced with the clinicians’ 
expertise and the patients’ life values and beliefs 
[329]. Evidence-based medicine may be 
considered as an interdisciplinary approach itself, 
which uses techniques from science, 
engineering, biostatistics, and epidemiology, 
such as meta-analysis, decision analysis, risk-
benefit analysis, verified case reports, and 
randomized controlled trials to deliver “the right 
care at the right time to the right patient” [330]. 
Every time that a physician treats a patient for 
anything, it is essentially a clinical trial with an “n” 
of 1. Thus the practice of evidence-based 
medicine tacitly dictates that physicians should 
make "conscientious, explicit, and judicious use 
of their understanding of the best medical 
information available" for the validation of the 
proposed treatment and its application in patient 
care in partnership with the patient and their 
expectations [331].  
 

Cancer is a serious and often life-threatening 
disease that deserves careful consideration of 
the benefits and long-term risks of each of these 
five strategic approaches, evolving beyond 
cohort-based trials into an integrated, 
personalized approach for the treatment of each 
patient. Champions for the exclusive use of any 
one of these strategies abound, but it is my belief 
and experience that the best answer for cancer, 
for any one patient, will be found in their 
integration into an individualized cohesive clinical 
protocol. 
 

Research is needed to codify the algorithm 
necessary for applying the best integrative 
therapeutic strategy given the dynamics of the 
cancer and the patient’s biochemistry, genetics, 
and immunology at any given point in their 
treatment. 
 

4. CONCLUSION  
 

Cancer, as a disease of our time, has been 
described as a “wound that does not heal” and is 
characterized as having numerous biochemical 
dysfunctions at its core, which lead to a multitude 
of genetic aberrations and pathologic phenotypic 
expression. However, in order for these 
genetically and phenotypically abnormal cells to 
survive and thrive, the watchdog of the body, the 
immune system, must itself be suffering from a 
number of serious areas of structural and 
functional damage. There are many tactics that 
can support the therapeutic strategies briefly 
described above, and they should be applied in 
an integrative manner as they are nonexclusive 



 
 
 
 

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17 

 

with each other and can be mutually supportive 
[332]. However, more aggressive cytotoxic 
strategies, i.e., full-dose chemotherapy and 
radiation, can render many of these strategies 
null and void but may be considered for possible 
later use. When treating cancer, the physician 
and patient should make the decisions together, 
since the stakes can be no higher, using the best 
information available at the time, and then never 
look back. When treating cancer there is but one 
direction to go and that is forward, striving for 
ever-increasing improvements in the quality and 
quantity of life with the hope of achieving a 
durable remission [333-336]. 

 
CONSENT  
 
It is not applicable. 
 

ETHICAL APPROVAL 
 
It is not applicable. 
 

ACKNOWLEDGEMENTS 
 
I would like to thank Summer A. Stoff, B.A., and 
Colleen A. Murtha-Stoff, N.P. for their highly 
valued editing skills in preparing this manuscript. 
 

COMPETING INTERESTS 
 
Author has declared that no competing interests 
exist. 
 

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