over again I find the malignant workings of pharma. Corporations vigorously
profits. It is no surprise to me that an excellent summation article with 35
references cannot find a journal willing to publish the manuscript. Why, because
this review article describes
the science behind starving cancer, and its success in treating cancer,
obesity, and epilepsy. So this article,
which should have made a prestigious journal, ends up being published in a free
on-line journal by Cornell University library.
scientific evidence base was established in 1924, is accepted by scientists
researching the metabolism of cancer, and is therefore not fringe
pseudo-science The damaged to the mitochondria became general knowledge among
oncologist when the future Nobel Laurite Otto Warburg published his seminal
paper on metabolism of cancer cells in 1924 and in it proposed starving the
cancer. The starving has been named the Warburg
(and thus oncologists) fail to act in the best
interest of patients is accurately describe in a 4-page article at http://healthfully.org/rep/id11.html. Even when the
evidence is presented to an audience of physicians most of will continue to
follow the pharma generated treatment guidelines. For a lecture to physician
on the ketogenic
diet given in a university by a professor click on link. This is an example
of the power of an $800
billion global industry to influence the practice of medicine including the
regulatory agencies. Some oncologist
(most of whom are practitioners and not researchers) are fully aware of the
Warburg effect (not merely of pharma’s tobacco science on cancer starvation)
and will assist their patient in going on a ketogenic diet. One count has placed
in the medical
literature over 1000 patients having tried the ketogenic diet, most with very
positive results. Unfortunate none of
them have the funds to run a clinical trial on cancer starvation.
Adam Kapelner, Matthew Vorsanger
Ketogenic diet as cure for cancer, review
Starvation of cancer via induced
ketogenesis and severe
Kapelner and Matthew Vorsanger Published by Cornell University Library.
http://arxiv.org/abs/1407.7622--entire, submitted on 29 Jul
2014 (v1), last revised 8 Dec 2014
Also at http://www.medical-hypotheses.com/article/S0306-9877(14)00398-3/abstract
and at http://www.mathpubs.com/detail/1407.7622v2/Starvation-of-Cancer-via-Induced-Ketogenesis-and-Severe-Hypoglycemia and
on Desk top folder, med UCSD.
Abstract Neoplasms [tumors] are
highly dependent on glucose as their substrate for energy production and are
generally not able to catabolize other fuel sources such as ketones and fatty
acids. Thus, removing access to
glucose has the potential to starve cancer cells and induce apoptosis.
Unfortunately, other body tissues are also dependent on glucose for energy
under normal conditions. However, in human starvation (or in the setting of diet-induced
ketogenesis), the body “keto-adapts” and
glucose requirements of most tissues drop to almost nil. Exceptions include
the central nervous system (CNS) and various other tissues which have a small
but obligatory requirement of glucose. Our hypothesized treatment takes
keto-adaptation as a prerequisite. We then propose the induction of severe
hypoglycemia by depressing gluconeogenesis while administering glucose to the
brain. Although severe hypoglycemia normally produces adverse effects such as seizure
and coma, it is relatively safe following keto-adaptation. [the coma from too
much insulin in diabetics occurs because their body hasn’t had time to switch
to fat metabolism, not a problem with induction phase and thereby raise serum
glucose to the normal level. In the full
article extremely low levels of serum glucose are obtained KD (ketogenic diet)
without side effects—jk.] We hypothesize
that our therapeutic hypoglycemia treatment has potential to rapidly induce
tumor cell necrosis.
PDF at http://arxiv.org/pdf/1407.7622.pdf Complete
2015, and on
Desk top folder, med UCSD.
In 1924, Otto Heinrich Warburg's
Nobel-prize winning research demonstrated that neoplastic cells rely on anaerobic
glycolysis for their metabolic needs. Almost a century later, the results and
implications of his _ndings are still hotly debated. It is now accepted that
most tumors derive the vast majority of their energy from glucose. This major
weakness is an attractive target for therapeutic intervention. However, basic
physiology dictates that normal cells would also be starved by severe
hypoglycemia. As such, targeting cancer by exploiting this metabolic weakness
has not been proven fruitful to date.1 In fact, cancer treatment has moved away from broadly
modalities towards highly targeted therapies (Aggarwal, 2010). Treatments of
choice include monoclonal antibodies, tyrosine kinase inhibitors, and induction
of specific immune responses as well as others. In this paper, we reexamine the
possibility of therapeutic hypoglycemia as an antineo-plastic treatment while
simultaneously delivering glucose to the body tissues that require it.
Our main hypothesis is that the alterations
in metabolism that occur in the starvation state, namely neurologic adaptation
to hypoglycemia, provide a means of safely inducing hypoglycemia. Of course,
this proposal is not mutually exclusive with other standard treatments such as
radiation, chemotherapy and dietary supplementation. The outline of the paper
is as follows.
Section 2 provides background on cancer cell metabolism and reviews the known
cytotoxic effects of hypoglycemia on cancerous cells. Here, we justify the
assumptions needed for our hypothesized treatment from the literature. The next
two subsections are prerequisites for understanding the implementation of our
hypothesized treatment. Section 3.1 discusses the body's theoretical minimum
glucose requirements during starvation as well as the concept of tissue keto-adaptation.
Section 3.2 discusses ketogenic dieting as a viable alternative to starvation
while retaining body-wide minimal glucose needs. We outline our severe
hypoglycemia therapy in detail in Section 3.3.
Section 4 concludes
and discusses further extensions
as well as potential concerns.
is the result of multiple changes in the
delicate balance of cell function. The root cause of neoplastic transformation
is still under serious debate. There are many theories: cancer is primarily
a genetic disease
(Vogelstein et al., 2013), cancer is a disease of aberrant metabolism due to
dysfunctional respiration in malfunctioning mitochondria (Seyfried and Shelton,
2010), cancer is due to overproduction of reactive oxygen species (Oleksyszyn
et al., 2014), as well as others.
of the cause, the majority of neoplastic cells feature an aberrant glucose
metabolism, first disvocered by Warburg et al (1924) and now know as the
“Warburg Effect”. [NORMAL CELLS
METABOLIZE GLUCOSE IN TWO STEPS]. First,
glucose is broken down to created pyruvate and a small amount of adenosine
triphosphate in the cytosol (glycolysis).
Second, pyruvate is shuttled into mitochondria where it is fully
oxidized to water and carbon dioxide in the Krebs cycle [Krebs did this
research in Warburg’s laboratory]. Even
with enough oxygen, cancer cells do not seem to advance beyond cytosolic
glycolysis to employ the vastly more efficient (by factor of 17 : 1) oxidative
phosphorylation. Instead, they divert
their pyruvate to produce lactic acid. This
is oxymoronically known as “aerobic glycolysis;” cancer cells ferment even in
conditions of normoxia [this sentence means that metabolism proceeds without
oxygen, and the term aerobic is the
opposite of what occurs, like giant
shrimp; normoxia means hypoxia,
without oxygen ]. A potential cause of
this aberrant metabolism is that cancer
cells only have a fraction of the mitochondria available to normal cells and
these mitochondria are structurally defective (see a review by Pedersen,
1977 and see Elliott and Barnett, 2011 for an electron microscopy study of
mitochondria from breast carcinoma). Others
say the cause is damaged glycolysis regulation (Koppenol et al., 2011).
Regardless, “all roads to the origin and progression of cancer pass through the
mitochondria" and the hallmark of cancer is oxidative phosphorylation to
varying degrees (Seyfried et al., 2014).
Regardless, all roads to the origin and progression of cancer pass
through the mitochondria" and the hallmark of cancer is malfunction in
oxidative phosphorylation to varying degrees (Seyfried et al., 2014).
implies that cancer cells do not have
access to non-glycolytic fuels that demand full oxidative combustion in the
Krebs cycle, namely fatty acids and the ketone bodies beta-hydroxybutyrate and
acetoacetate (Holm et al., 1995, Sawai et al., 2004), two substrates that are
key players in our hypothesized treatment. Chang et al (2013) demonstrated that
cells [neuro cells, glial or glia cells, non-neuronal cells that maintain
homeostasis in the nervous system] in their investigation lack enzymes that
break down ketones. Such evidence may explain
why introduction of healthy
mitochondria into cancer cell cytoplasm halts carcinogenesis (see Seyfried,
2012, Chapter 11 for a review of these studies).
The relevant point to our
hypothesis is that glucose is the predominant energy substrate for most cancers (Gullino et al. 1967) with glycolytic rates
[metabolism of glucose] 8-200 times higher than normal tissues (Phelps, 2004,
Chapter 5) while producing about 10% more ATP than normal cells (Koppenol et
al. 2011). Cancer has a large fuel
requirement due to its high proliferation rate and large need for antioxidants. In
addition, high glucose consumption is
necessary for intermediaries required in biosynthetic pathways: ribose for nucleotides;
and citrate for lipids; amino acids and nicotinamide adenine dinucleotide
phosphate (NADPH) via pentose phosphate pathway (Dederardinis et al., 2008)
being the exclusive source of energy in cancer is hotly
debated and may not be true of all cancers throughout their lifespan; tumors
may have varied bio-energetic profiles. [Pharma’s
KOLs (key opinion leaders) do tobacco science and debate the merits of KD; thus
they promote drug treatments.] They may
be glycolytic and/or oxidative (Jelluma et al., 2006; Moreno-Sanchez et al.,
2007; Martinez-Outschoorn et al., 2011; Jose et al., 2011; Carracedo et al.,
2013). For the purpose of this
article, we address the majority of
neoplasms which the consensus holds are exclusively glycolytic. We await future research that will elucidate
when and in which cancer lines our hypothesize treatment is most
cancer should be particularly vulnerable to glucose/glycolytic substrate
deprivation. Starving cancer from
glucose is not a novel idea; proposals to treat cancer via serum hypoglycemia
date back to an editorial in the New York Times (1887) and are abundant in the
recent literature (Woolf and Scheck, 2014; Simone et al., 2013; Fine et al.,
2012, 2008; Seyfried et al., 2008; Mavropoulos et al., 2006; Kim et al., 1978). Another
idea would be to inhibit glycolysis (e.g. Ganapathy-Kanniappan et al., 2010)
but this is not the strategy we propose due to its more universal cytotoxicity
[major side effects].
though the idea of cancer starvation is commonplace, there are no well-designed
studies evaluating this premise…. Financial
concerns are also a likely explanation.… With
the time and resources needed to produce
a high-quality clinical trial, it is unlikely that therapeutic hypoglycemia
would produce an adequate
return-on-investment for a pharmaceutical company…. There are many uncontrolled
studies that are
optimistic. For example, Zuccoli et al. (2010) details the account of a woman
who had spontaneous remission (i.e. sudden disappearance of cancer) of
glioblastoma multiforme after two months on a diet formulated to lower serum
glucose. Niakan (2010) concluded that over
1,000 similar spontaneous remissions are most likely due to hypoglycemia and
hypoxia [lack of oxygen] (arguably a direct consequence of the hypoglycemia).
animal studies demonstrate promising
results by cutting cancer's nutrient supply (Mukherjee et al., 2002, 2004;
Zhou et al., 2007; Otto et al., 2008; Mavropoulos et al., 2009; Shelton et al.,
2010; Stafford et al., 2010; De Lorenzo et al., 2011; Sivananthan, 2013; Jiang
and Wang, 2013). However, there are some studies that are inconclusive (e.g. Masko
et al., 2010). However, there are some
studies that are inconclusive (e.g. Masko et al.,2010) [probably a pharma’s
are many creative in-vitro studies of glucose starvation. In Demetrakopoulos
et al. (1978), tumor cells
were found to be highly sensitive to glucose deprivation. Spitz et al. (2000) found
that glucose withdrawal induces cytotoxicity in transformed broblasts and colorectal
cells, which they
argue is the result of oxidative stress. Buzzai et al. (2005) demonstrated that
activation of the commonly expressed oncogene Akt prevents cancer cells from
metabolizing non-glycolytic substrates. Jelluma
et al. (2006) perfomed the first study of glucose withdrawal on glioblastoma
multiforme cells and found 90% cell death in 24 hours. The death was not due
to ATP depletion and
could be rescued by a free radical scavenger, thereby lending credence to the
oxidative stress theory. Aykin-Burns et al. (2009) demonstrated that glucose
deprivation can induce cytotoxicity in human breast cancer cells and colon
cancer cells in-vivo. They argue these
results are due to cancer being unable to synthesize reducing agents such as
NADPH and pyruvate which are needed en masse for detoxication of high concentrations
of free radicals due to mitochondrial abnormalities. Li et al. (2010) observed growth
inhibition and apoptosis in lung broblasts
after glucose restriction and Priebe et al. (2011) demonstrated cell death in
ovarian cancer. Also, Graham et al. (2012) demonstrated that glucose withdrawal
slows the proliferation, induces hyperthermia, and possibly induces cancer cell
death in four gliobastoma cell
proposal is a natural extension of previous cancer starvation proposals. We
propose a ketogenic diet which allows for the safe induction of severe hypoglycemia
via gluconeogenesis attenuation. The serum levels we propose are lower than
have ever been proposed in the past and we do so in order to starve cancer
cells rapidly. We now turn to detailing this therapy.
3 Our hypothesis
next two sections provide background material about human starvation and
ketogenic dieting that is necessary for understanding our hypothesized
treatment which we detail in Section 3.3
3.1 Starvation: Minimizing the
Body's Glucose Needs
The body’s glucose requirements are minimized during periods
of starvation, which constitutes drastic transformation in the body’s energy
metabolism. Broadly speaking starvation
has five stages which are outlined in the Table 1 below.
Normally by the end of the first day, hepatic glycogen stores
are depleted and the liver (and to a lesser extent, the kidneys) begin to
produce glucose from pyruvate, glycerol and amino acids. The vast majority of
tissues in the body (such as skeletal muscle, the heart, and most organs) are
facultative in their choice of substrate for energy production. During this period
of glucose scarcity, they cut their glucose metabolism and increase their
metabolism of free fatty acids (FFAs). Starvation
even at this early stage forces body tissues to switch from glycolysis to lipid
oxidation for their energy needs. The ketone bodies Beta OHB, acetoacetate and
acetone are always present in the blood, but after a few days of starvation
they begin to be produced in large quantities in the liver. Most tissues of the
body can metabolize ketones (with the exception of acetone).
gluconeogenesis and increased cerebral
The five stages of starvation from the time of last ingestion
(reprinted from Cahill, 1983, page 2).
Of special interest is stage 5--prolonged starvation of two
weeks and longer. Cells have long since cut their uptake of glucose but now
also cut their uptake of ketones. This
change, coupled with increased blood-brain-barrier permeability of ketones (Morris,
2005) we will call keto-adaptation." During stage 5, most cells rely
purely on FFAs for their metabolic requirements (Robinson and Williamson,
1980). However, some tissues still
retain a need for glucose even after keto-adaptation. The largest consumer is the
brain and CNS, whose health is vital to
the success of our hypothesis.
How much glucose does the brain need? A typical
brain glucose requirement (Cahill,
1970, Figure 1). This is a preferential
utilization but not an obligatory utilization. This point is crucial to our
hypothesis. During keto-adaptation, the brain
glucose requirement drops to approximately 44 g/day (Cahill, 1970, Figure 5).
What supplies the energy that this difference of
approximately 100 g/day of glucose previously supplied? [The brain consumes
about 150 g/day of
glucose.] The ketone bodies -OHB and acetoacetate in a 6:1 proportion (Owen et
al., 1967, Table 5). Note that the brain
does not metabolize FFAs (Owen et al., 1967, Table 4). In stage 5 starvation,
ketone blood levels
surge to 2.5-9.7 mmol/L which are in contrast to a negligible level of .01
mmol/L in non-starving subjects. The
brain will readily use ketone bodies if they are available even in non-fasting
periods, but under this condition ketone usage is negligible (Sokolo , 1973).
Morris (2005) suspects that the brain's ketone
metabolism was evolutionarily developed to ensure survival in times of glucose
being scare. Cahill (1970) suspects that
other body tissues slash their ketone consumption in favor of FFA's to ensure
adequate substrate for the brain. Further, Cahill and Veech (2003).
The fuel metabolism of stage 5 starvation is illustrated in
Figure 1. Of special interest is the inventory of the sources of
gluconeogenesis that provide the 44 g/day CNS requirement: stored triacylglycerols
(15g), amino acids
taken from muscle tissue and to a lesser extent other tissues (20g), and
pyruvate / lactate (14g), which is the end product of anaerobic glycolysis (thus
about a third of the glucose during starvation burned by the CNS is recycled
back into glucose via the Cori cycle).
The figure of 24 hours
Basal Metabolism (~`,500 CAL) won’t copy
Figure 1: Fuel sources and
sinks in the daily metabolism of Stage 5 starvation assuming a
1500 calorie resting metabolism (inspired by
Cahill, 1970, Figure 5).
Starvation can be a useful tool to minimize glucose needs in
all but a few body tissues. Fasting,
while relatively safe (Stewart and Fleming, 1973), is not only unpleasant but
leads to muscle wasting and weight loss, both of which are serious concerns in
cancer patients. How do we minimize the
body's glucose needs while avoiding these undesired effects? We turn to a
solution in the next section.
3.2 Keto-adaptation via the 4:1
A means to emulate the metabolic conditions of starvation
while still ingesting food is the same engineering problem faced in the 1920's
by the expert childhood epileptologist Dr. Russel M. Wilder. He observed that
short-term starvation was therapeutic for children with intractable epilepsy,
but obviously impractical as a long-term solution. He innovated the “ketogenic
diet" (KD) that mimics the characteristic starvation metabolism we
outlined in Section 3.1. It is still used today to reduce seizures (for an historical
account and a recent clinical
trial, see Neal et al., 2008).
Wilder's KD is a high fat, low protein and very low
carbohydrate diet (McDonald, 1998). In
what is called the “4:1 KD," carbohydrate must be limited to 20 g/day (the
amount the muscle tissue provides during prolonged starvation) and protein must
be limited to an amount to offset normal (non-starvation) protein turnover,
estimated at about 25 g/day for a 70kg person (National Research Council (US)
Food & Nutrition Board, 1989). Any additional protein has the potential to
be gluconeogenic and thereby should be avoided.
All other calories must be supplied by fats.5 Commercial
formulas for this diet are readily available.
Are the physiological markers in a prolonged 4:1 KD exactly
the same as markers under prolonged starvation? Depending on the macronutrient
proportions, serum glucose can be slightly higher and ketone levels slightly
lower (Phinney et al., 1983). We assume that a 4:1 KD is equivalent to
keto-adapted metabolism observed during prolonged starvation described in
Section 3.1: glucose uptake minimization, increased cerebral ketone uptake, and
exclusive use of FFAs for energy production in every other tissue in the body.
Thus, a KD can achieve starvation metabolism adaptation without the unpleasant
side effects of hunger and muscle loss.
et al. (2013) also reviews other benefits of the KD such as muscle sparing and
possible even muscle synthesis which can be beneficial for cancer patients with
risk of cachexia. The KD is generally well-tolerated
with minimal side effects such as constipation, salt loss, mild acidosis and
increased incidence of kidney stones, when employed chronically" and has been
demonstrated to be safe even in patients with advanced cancer (Schmidt et al.,
2011). Kossoff et al (2007) reports on
the longest duration of a KD: 21 years with virtually no side effects. There
is also some evidence that ketones in
their own right are directly toxic to cancer (Magee et al., 1979; Skinner et
al., 2009; Fine et al., 2009) and can improve the immune system's ability to
target cancer (Husain et al., 2013). This can be an added benefit of the KD
that can work in tandem with our hypoglycemia strategy.
hypothesized treatment begins with a cancer patient being administered a 4:1 KD
for more than 14 days to allow for keto-adaptation. Then our proposed acute
treatment is begun. We turn to implementation details now.
3.3 Our Proposed Treatment
Section 2 discussed previous literature that experimented
with both starvation and the KD for cancer therapy via glucose starvation. We
believe these studies did not reduce serum
glucose to levels sufficient to starve cancer.
On a KD, “plasma glucose concentration fall only mildly, remaining in
the normal range in normal-weight individuals ... [thus] ... simple tumor
glucose starvation is therefore unlikely in humans" (Fine et al., 2008).
Serum glucose in prolonged starvation drops to about 65mg/dL
(Cahill, 1970, Table 2) and the prolonged 4:1 KD can also result in a similar
serum level, but it is unclear why further reduction in the blood glucose level
should not be similarly well-tolerated after keto-adaptation.
In an adult, cerebral blood flow is approximately 750mL/min =
0.13 dL/s which implies 8.1mg/s of glucose can potentially be delivered to the
brain. In Section 3.1, we noted that the brain has an obligatory requirement of
44 g/day = 0.51 mg/s6 which is only 6% of the glucose available at a serum
concentration of 65 mg/dL. Although experiments evaluating the glucose
extraction ratio in human subjects are limited, animal studies suggest that the
brain is able to extract 40% of the serum glucose in the hypoglycemic state
(McCall et al., 1986). Thus, we theorize that the body is being conservative.
Serum glucose concentrations below the level where 0.51 mg/s can be actively
transported into neurons for mere moments can result in CNS damage; 65 mg/dL is
comfortably above this threshold.
We have evidence for this conjecture that
keto-adapted subjects can survive on serum glucose much lower than 65mg/dL.
Hypoglycemia has been reported in therapeutic fasting or starvation for over
100 years. Chakrabarty (1948) investigated 407 starvation cases in Bengal
famine to find that 20 or so of them had chronic blood sugar below 40 mg/dL with no symptoms of hypoglycemia… We
have evidence for this conjecture that
keto-adapted subjects can survive on serum glucose much lower than 65mg/dL.
Hypoglycemia has been reported in therapeutic fasting or starvation for over
100 years. Chakrabarty (1948) investing ated 407 starvation cases in the Bengal
famine to _nd that 20 or so of them had chronic blood sugar below 40 mg/dL with
no symptoms of hypoglycemia. Stewart and Fleming (1973) who supervised a
world-record-setting 382-day therapeutic fast found that blood glucose became
stable at 30 mg/dL, dropping intermittently to 20 mg/dL without symptoms. The
most relevant evidence to our hypothesis is the observation of intentional
acute hypoglycemia induction by Drenick et al. (1972) who keto-adapted obese
patients via 45-60 days of starvation and then perfused insulin. Within the
hour, they observed serum glucose as low as 9 mg/dL without acute hypoglycemic
symptoms. Serum glucose this low would normally induce coma (which has even
been observed with blood sugar as high as 40-49 mg/dL according to Ben-Ami et
al., 1999, Figure 3).
Our plan is simple. After keto-adaptation with the 4:1 KD, we propose to
acutely attenuate the serum glucose concentration to severely hypoglycemic
levels such as observed in Drenick et al. (1972) on a patient-by-patient basis.
Since insulin is required by cancer cells and fuels their metabolism (Iqbal et
al., 2013) and also can impede ketogenesis, we choose not to induce
hypoglycemia via insulin perfusion (as in Drenick et al., 1972), but instead propose
the use of a gluconeogenesis inhibitor.
One possible inhibitor is the diabetic drug metformin which inhibits
gluconeogensis indirectly. Metformin may have other anti-cancer effects
(Jalving et al., 2010, Figure 3) and there is certainly supporting
epidemiological evidence for metformin's therapeutic effect in cancer (Ben
Sahra et al., 2010). For these reasons, it has been proposed for use in a hypothesized
treatment similar to ours (see Oleksyszyn, 2011 and further in Oleksyszyn et
al., 2014). However, metformin has many drawbacks. First, it is not a potent
inducer of hypoglycemia in the doses that are normally administered. Metformin
is also slow acting and not rapidly titratable. Additionally, the drug
activates adenosine monophosphate activated pro tein kinase which may have
other effects on metabolism under keto-adaptation (see Jalving et al., 2010,
Figure 2). Lastly, supratherapeutic doses have been associated with fatal
Due to these shortcomings, we propose using a drug which is a pure
liver-kidney gluco-neogenesis inhibitor. Luckily, these drugs have been
investigated by the diabetes community where high endogenous glucose production
is considered one of the characteristics of the disease and is therefore a
There are many control points within gluconeogenesis. The unidirectional
synthesis of fructose-6-phosphate from fructose-1,6-bisphospate is a prudent
point to interrupt because it is removed from glycogenolysis and mitochondrial
function (thus, it would have the fewest side effects). The synthesis is
controlled via the rate-controlling enzyme fructose-1,6-bisphosphatase. Two
inhibitors that have been clinically evaluated are named CS-917 and MB07803
(van Poelje et al., 2011). They have good safety profiles and can flexibly
gluconeogenesis to any desired level.
Returning to our discussion of the target level of hypoglycemia, we
comment that we do not know the effective dose (ED) curves for serum glucose
levels for tumor necrosis or the or lethal dose (LD) curves for human body
death after keto-adaptation. It is possible that a 9 mg/dL glucose
concentration may be too high to be toxic for the cancer. If this proves to be the
case, further hypoglycemia would need to be safely induced for treatment effcacy.
We turn to this now.
Since the brain is the only tissue with an obligatory glucose requirement,
we opt for direct perfusion of glucose into the brain intra-arterially via the
carotid arteries at the rate necessary to provide minimum brain glycolytic
needs. Perfusion of glucose directly to the brain has been performed
successfully in rats (Borg et al., 1997) and baboons (Conway et al., 1969).
Once the brain receives its required glucose, we propose an increase in the dose
of gluconeogenic inhibitor drug to attenuate serum glucose to a negligible
level which is safe enough for erythocytes, blood marrow and leukocytes to
survive. The brain would perceive normoglycemia but everywhere outside of the
brain the serum would be extremely hypoglycemic. If necessary, we can also
perfuse _-OHB in tandem if there is risk that the level
of ketosis is not su_ciently high for CNS metabolic needs. This protocol would
require extensive proof-of-concept work in animal models before any attempt to
undertake study in human subjects.
The reader may wonder if this strategy would be e_ective against brain
cancer since the brain is still receiving glucose. Seyfried et al. (2003)
reports data supporting that such a treatment may be e_ective since glucose
uptake in brain cancers drops with lower serum glucose and that the cancer
cannot metabolize ketones, which may even be toxic to them. How fast could this
procedure induce tumor
death? We echo Oleksyszyn et al. (2014), “we do not have any idea as to how
deep hypoglycemia needs to be to trigger spontaneous remission." All
estimates are drawn from data from in-vitro studies and
thus are not generalizable to human prognoses. Spitz et al. (2000, Figure 2)
reports between 55% and near 100% necrosis rates in three cancer lines within
48hr after total glucose deprivation. Complete withdrawal is not possible in
the human body for reasons explained above and our treatment could deliver
minimum serum levels estimated at 5 mg/dL.
How fast could this procedure induce tumor death? We echo Oleksyszyn et
al. (2014), “we do not have any idea as to how deep hypoglycemia needs to be to
trigger spontaneous remission." All estimates are drawn from data from in-vitro studies and thus are not generalizable to human prognoses.
Spitz et al.
(2000, Figure 2) reports between 55% and near 100% necrosis rates in three
cancer lines within 48hr after total glucose deprivation. Complete withdrawal
is not possible in the human body for reasons explained above and our treatment
could deliver minimum serum levels estimated at 5 mg/dL.
[They propose direct infusion of glucose via the carotid
artery and block glucose in the body with a drug similar to metformin. I doubt
the need for this radical intervention.] This protocol would require extensive
proof-of-concept work in animal models before any attempt to undertake study in
human subjects. … Spitz et al. (2000, Figure 2) [in vitro] reports between 55%
and near 100% necrosis rates in three cancer lines within 48hr after total
We propose a therapy for starving cancer by
inducing keto-adaptation followed by the induction of therapeutic hypoglycemia
via gluconeogenesis inhibitor drugs. We then propose rescue cerebral glucose
infusion through direct catheterization of the brains's blood supply. This would
be followed by an increase of the
gluconeogenic inhibitor drug to lower serum glucose even further in
A main concern is that each person is a
\unique metabolic entity" (Seyfried et al., 2014). The calculations presented
manuscript are meant to be illustrative of an average person. For each
individual, personalized dosing and administration schedules will require
Proper monitoring and its associated costs
are a concern. Hypoglycemia is very risky but might not necessarily require the
monitoring setting of an intensive care unit (patients with diabetic
ketoacidosis are frequently treated with insulin infusion outside of the
intensive care unit). Although the costs of the diet and the medications needed
to induce hypoglycemia in our proposal might be far lower than the cost of
novel chemotherapeutic agents, the cost of close monitoring may substantially
erode this benefit.
There are several other concerns with
speculative treatment. Cancer is
heterogeneous and few predictors are currently available as to an individual
tumor’s response to hypoglycemia. There
is research suggesting that some cancer cells can make use of ketones and
FFAs. Not all cancer lines proliferate
rapidly and intense anabolism is not mandatory (Jose et al., 2011. Our
hypothesized treatment would not work in such cancer lines. It is
not known whether the proposed hypoglycemic levels can be sustained for long
periods of time without symptoms. Starvation research suggests that
hypoglycemia is safe in the long term, but these accounts documented serum
levels many times above our proposed serum level and they were predominantly
documented in obese subjects without cancer. An important consideration is
whether keto-adaptation additionally protects against the neuro-hormal
cardiovascular and electrophysiologic consequences of hypoglycemia (Frier et
al., 2011). Additionally, glucose is not the sole
nutritive substrate for cancer cells. For instance, glutamine
can also serve as a major
metabolite (Yuneva, 2008), as well as fermentation from other amino acids. There
are times when the body is in need of
glucose such as during inflammation and infection which limits the setting of
our hypothesized treatment.
There is also a fair chance that our proposed treatment is
more effective when provided in tandem with other therapies. For instance,
Abdelwahab et al. (2012) demonstrated that brain cancer in mice was curtailed
and did not recur with the simultaneous administration of the 4:1 KD and
radiation therapy. Allen et al. (2013) demonstrated that the 4:1 KD enhances radio-chemo-therapy
in mice models of lung cancer. See Klement and Champ (2014) for a discussion of
how the KD can act synergistically with radiation therapy. Also, Lee et al. (2012)
demonstrated that fasting enhances chemotherapy. Poff et al. (2013) demonstrated
oxygen therapy is enhanced by the KD.
Alternative adjuvant therapies may also be fruitful. For
example, Majumdar et al. (2009) demonstrated that the combination of curcumin
with resveratrol could be an effective therapy in colorectal cancer, Singh and
Lai (2004) demonstrated cancer apoptosis from wormwood extract and Tin et
al. (2007) demonstrated that astralagus saponins
can inhibit colorectal cancer cell
proliferation. There are many other such supplements that can be
administeredsimultaneously with our hypoglycemia treatment.
We would like to thank Justin Bleich and Stephen Kapelner for helpful
discussions and comments on this manuscript. We would like to thank Marie Le
Pichon for illustrating Figure 1. Adam
Kapelner acknowledges support from the
National Science Foundation's Graduate Research Fellowship as well as support
from the Simons Foundation Autism Research Initiative.
is not known if the average brain can do with less than 44 g/day of glucose. We
assume that if the body can get away with providing less, it would do so. Why?
Each gram of glucose conserved is one gram of protein conserved. Protein
sparing is essential during starvation since protein is man's precious
machinery vital to cellular structure and function. Depletion of these reserves
can limit long-term survival even with massive lipid depots. This question can
also be asked as follows: why are ketones unable to provide 100% of the brain's
energy requirements? The answer is unknown and we posit two theories. First,
there may be
incomplete -OHB and acetoacetate transport
cells of the CNS (Morris, 2005). Second,
-OHB and acetoacetate can only be converted to energy via oxidative
phosphorylation in mitochondria; these organelles are scant in long and thin
myelinated axons (Waxman et al., 1995, page 17). Here, we posit that some of
the brain's energy production must default to glycolysis in the axoplasm.
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