Examining the relationship between diet-induced
acidosis and cancer
Ian Forrest Robey*
Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance
over time. Acidogenic diets, which are typically high in animal protein and salt and low in fruits and vegetables,
can lead to a sub-clinical or low-grade state of metabolic acidosis. The relationship between diet and cancer risk
prompts questions about the role of acidosis in the initiation and progression of cancer. Cancer is triggered by
genetic and epigenetic perturbations in the normal cell, but it has become clear that microenvironmental and
systemic factors exert modifying effects on cancer cell development. While there are no studies showing a direct
link between diet-induced acidosis and cancer, acid-base disequilibrium has been shown to modulate molecular
activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling,
dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream
effectors of carcinogenesis or tumor promotion. In short, diet-induced acidosis may influence molecular activities at
the cellular level that promote carcinogenesis or tumor progression. This review defines the relationship between
dietary lifestyle and acid-base balance and discusses the potential consequences of diet-induced acidosis and
cancer occurrence or progression.
Keywords: Acid-base balance, Diet, Acidosis, Cancer
Diet, cancer, and ‘acidity’
The relationship between diet and cancer is well known
[1-3]. Dietary intake exists as the largest external or en-
vironmental epigenetic factor capable of driving the de-
velopment or maintenance of cancer. The American
Institute for Cancer Research (AICR) comprehensive
global report has compiled numerous studies demon-
strating associations between dietary habits and cancer
risk . The findings recommend increased or regular
consumption of vegetables, fruits, whole grains, and
legumes, while discouraging excess consumption of sug-
ary and energy-dense foods and drinks, red and pro-
cessed meats, and salty processed foods (www.aicr.org).
Acidity is a well known factor associated with cancer.
Lower pH levels in the extracellular space promote the
invasive and metastatic potential of cancer cells [5-14].
Extracellular acidity is mostly generated by tumor cells
due to upregulated proton [H+] and lactic acid produc-
tion . This phenomenon is distinct from ‘acidity’
caused by a net-acid diet. A net-acid diet or acidogenic
diet is determined by the balance between acid and
base-forming dietary constituents. Most fruits and vege-
tables are net-base producing foods since the metabo-
lized products are organic anion precursors such as
citrate, succinate, and conjugate bases of carboxylic acids
[16-18]. The final metabolite of these precursors is bicar-
bonate anion. Sulfur containing amino acids, methionine
and cysteine, typically found in meats, eggs and dairy
products, are oxidized into sulfuric acid which is ultim-
ately net-acid producing . Cationic amino acids such
as lysine and arginine can be acid producing if their an-
ionic counterpart is chloride, sulfate, or phosphate.
However, if the anionic component is a metabolizable
organic acid (glutamate or aspartate), there is almost no
impact on systemic acidity [17,18]. Other dietary factors are
known to influence acid-base status as well. Sodium chlor-
ide is reported to be an independent and causal factor for
inducing metabolic acidosis in a dose-dependent manner
[19,20]. Conversely, potassium salts, and to a lesser degree
magnesium, serve as a countervailing effect on net acid
excretion and help to promote alkaline balance [21,22].
Arizona Respiratory Center, University of Arizona, 1501 N. Campbell Ave.,
Suite 2349, PO Box 245030, Tucson, Arizona 85724, USA
© 2012 Robey; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Robey Nutrition & Metabolism 2012, 9:72
Acidogenic dietary intake such as high protein con-
sumption can have an immediate effect on increasing
net acid production while low protein lacto-vegetarian
consumption can result in significantly reduced net acid
excretion [23,24]. Short-term dietetic acid loading may
cause temporary acid-base disequilibrium, but is quickly
compensated and has no measureable clinical effect. A
persistent acidogenic diet, however, raises the likelihood
of an increased [H+] surplus and chronically lower levels
of serum bicarbonate if compensatory processes become
less efficient and are unresolved by dietary adjustments.
Potential long-term effects of acidogenic diets are fur-
ther compounded by the reduction of renal function typ-
ically from ageing [16,25-28].
Blood pH from prolonged or chronic acidogenic diets
is reported to be near the lower physiological range
(7.36-7.38) rather than the higher end (7.42-7.44). Spe-
cifically, persistent acidogenic diets have the potential to
cause small decreases in blood pH and plasma bicarbon-
ate, but not beyond the normal physiological range. This
condition is described as ‘diet-induced’, ‘low-grade’, or
‘chronic metabolic acidosis’ [28-30] or sometimes ‘latent
acidosis’ . Diet-induced acidosis is distinct from clin-
ical metabolic acidosis in that clinical metabolic acidosis
occurs when factors other than just acidogenic diet con-
tribute a system’s inability to compensate for blood [H+]
perturbations, typically resulting in blood pH below 7.35
. The patho-physiological effects of clinical metabolic
acidosis are well known , while the true pathophysio-
logical impact of long-term, diet-induced acidosis is not
well understood. For example, it is unknown if [H+] ac-
cumulation from chronic diet-induced acidosis can be
stored at the cellular level if it does not play a role in
lowering blood pH or is compensated by competent
renal or respiratory function. Studies of the impact of
clinical metabolic acidosis on biological systems may still
be informative towards understanding the effects of diet-
induced acidosis because they examine how acid-base
disequilibrium causes physiological stress and influences
molecular pathways active in disease processes .
It is generally understood that the cancer condition
evolves from genetic and epigenetic changes in the normal
cell. Both microenvironmental and systemic factors exert
selective pressures that aid in the initiation or aggravation
of tumors. Acid-base disequilibrium is considered a type
of systemic stress. With the understanding that long-term
acidogenic diets potentially exert chronic physiological
stress, the question proposed here is: Can diet-induced
acidosis increase cancer risk or promote existing tumors?
Cortisol and acid-base balance
Acid-base balance in the body influences adrenal hor-
mone production of cortisol. When bicarbonate [HCO3
levels are low the kidneys upregulate glutaminase activity
and trigger cortisol production [35-37]. Studies in animals
and humans have reported that system cortisol levels are
enhanced by acid-base disruption through transiently
induced metabolic acidosis . Acidosis appears to medi-
ate cortisol activity through the pituitary-adrenal cortex-
renal glutaminase I axis . Dietary induction of acidosis
increases serum cortisol concentrations . In healthy
adult humans serum and salivary cortisol is increased sig-
nificantly within hours after a high protein meal, and cor-
tisol levels were dependent on the protein content of the
The converse to these findings is shown in a study
designed to neutralize the acidogenic effect of the
‘Western’ diet, characterized by a high consumption of
meat, salt, sugar and fat, and proportionately lower intake
of fruit, vegetables, and whole grains. The relationship to
cortisol levels and acid-base status were examined in
six healthy men and three women measuring serum
and urine cortisol concentrations along with cortisol
metabolite levels (tetrahydrocortisone and tetrahydrocor-
tisol) in the urine of individuals with sodium and potas-
sium chloride replaced with equimolar amounts of
sodium and potassium bicarbonate in an otherwise
similar diet under “metabolic ward conditions”. Within
24 hours, urinary and plasma cortisol and correspond-
ing metabolites were significantly lower, signaling lower
cortisol production and activity. Urinary pH and serum
Not all studies report a positive correlation between
high protein, potentially acidogenic diets, and cortisol
levels. These studies did not assess acid-base balance in
their experimental populations so it is difficult to con-
firm if these studies are directly comparable to findings
linking acidogenic dietary intake and increased cortisol
production. It is likely that factors such as gender and
body mass index are relevant inconsistencies between
various reports [42-44].
Many of these studies suggest there may be a role for
diet-induced acidosis in modulating systemic cortisol
levels, and that neutralization of acid loading through
alkalinization may reduce cortisol levels. Moreover, most
of the studies evaluating the role of acidogenic intake on
cortisol demonstrate that the interventions had an acute
and dose-dependent effect on cortisol levels, suggesting
a direct or closely linked dynamic between acid-base sta-
tus and system cortisol levels. Finally, the studies show
that diet-induced acidosis is mild and subsequent induc-
tion of cortisol activity, although higher in serum con-
centration, is sub-clinical and within the normal serum
range . If there were pathophysiological conse-
quences it could only be derived from chronic or persist-
ent conditions maintained on an acidogenic diet.
-] levels increased while serum pH remained
Robey Nutrition & Metabolism 2012, 9:72
Page 2 of 11
Cortisol bioactivity in cancer
There is no clear mechanism linking cortisol bioactivity
directly with carcinogenesis, but studies have reported
that cortisol signaling may exert biological influence on
existing tumors. Androgen-independent prostate tumors
expressing high levels of androgen receptor can be
stimulated by cortisol and its metabolite cortisone,
resulting in growth promotion and proliferation. The
mechanism for this interaction is made possible due to a
mutation in the androgen receptor that favors ‘promis-
cuous’ binding of additional signaling molecules like
glucocorticoids . In some breast cancer studies glu-
cocorticoids suppress growth by blocking cell cycle pro-
gression . Tumor inhibition appears to be androgen
dependent at least in some cell lines [47,48]. In colon
cancer, cortisol signaling inhibits 11β-hydroxysteroid de-
hydrogenase 2 (11βHSD2) enzymatic activity which pre-
vents activation of the COX-2 tumor promoter, an early
activation marker for colon carcinogenesis. The diversity
of tumor responses to glucocorticoid signaling suggests
that the relationship between hormonal activity and
tumor regulation is receiver-dependent. The following
sub-sections discuss the possible indirect role of cortisol
signaling in cancer risk and carcinogenesis.
Cortisol and tryptophan metabolism
Cortisol activates the tryptophan metabolism pathway
which is carried out by rate-limiting enzymes of trypto-
phan catabolism, 2,3-dioxygenase (TDO) and indolea-
mine 2,3-dioxygenase (IDO). Cortisol directly stimulates
TDO activation and may augment IDO activity indir-
ectly through inflammatory cytokine signaling such as
interferon gamma [49,50]. Excessive or chronic cortisol
production acquired from a ‘Western’ dietary lifestyle
could play a role in augmenting the tryptophan metabol-
ism pathway and drive downstream molecular events
that promote carcinogenesis.
The product of TDO and IDO activity, kynurenine, has
several roles in promoting tumorigenesis. Kynurenine
inhibits the activation of effector T-cells when tryptophan
levels are low. Incapacitating effector T-cell function is
suggested as an important component in increasing vul-
nerability to tumor development [51-53]. Tryptophan me-
tabolism also promotes immune tolerance of professional
antigen presenting cells (APCs) which are critical in acti-
vating other immune cells [51,53,54]. Finally, kynurenine
binds to aryl hydrocarbon receptor (AHR), which med-
iates TDO and IDO signaling in regulatory T-cells. The
activated AHR suppresses the stimulation of regulatory
T-cells involved in inhibiting early tumor development
[51,55-57]. The connection between diet-induced, low-
grade hypercorticoidism and the effect on tryptophan me-
tabolism to subsequently promote tumor development
has not been adequately explored. Furthermore, it is
unknown what other factors may enhance, regulate, or at-
tenuate these signaling events, but a persistent reduction
of effective immune surveillance capability promoted in-
directly by diet-induced acidosis could cultivate microen-
vironmental conditions favorable for oncogenic cells to
develop metastatic potential.
Cortisol and insulin resistance
Upregulated cortisol bioactivity driven by diet-induced
acidosis may be a factor in metabolic syndrome by pro-
moting insulin resistance. Chronic hyperglucocorticoid-
ism upregulates visceral obesity while reducing insulin
sensitivity mainly in visceral adipocytes which appear to
be more responsive to cortisol than subcutaneous adipo-
cytes due to higher expression levels of glucocorticoid
receptors [58,59]. Visceral adipocytes also exhibit greater
11βHSD1 activity, which converts cortisone to bioactive
cortisol . Glucocorticoids stimulate visceral adipo-
cytes to increase the activity of lipoprotein lipases, while
simultaneously suppressing insulin mediated glucose up-
take [61-66]. This phenomenon suggests that cortisol
activated adipocytes are less efficient in storing fatty
acids which tend to increase the level of free fatty acids
in circulation and contributes to diminished insulin sen-
Glucocorticoid signaling promotes insulin resistance
through other signaling pathways as well. Insulin stimu-
lated glucose transporter-4 (GLUT-4) translocation to the
cell surface of adipose tissue is suppressed by glucocorti-
coids. Cortisol directly inhibits insulin secretion from pan-
creatic beta cells. Finally, cortisol can reduce insulin
mediated vasodilation of endothelial cells, and suppresses
peripheral insulin driven glucose uptake [68-70].
Acidosis associated insulin resistance through cortisol
activity may result in compensatory pancreatic insulin
secretion and higher levels of circulating insulin in the
serum, a condition known as hyperinsulinemia. Epidemi-
ology studies have shown a positive correlation between
circulating insulin levels and increased risk and patho-
genesis of colorectal and pancreatic cancers [71-76], can-
cers of the endometrium , kidney cancer  and
breast cancer [79,80]. Longitudinal studies report a
higher risk for breast cancer in women with hyperinsuli-
nemia [81-83]. Human studies are confirmed by experi-
mental data showing that injected insulin promotes
tumorigenesis in animal models for colon  and
breast [85,86] cancer. Insulin deficiency or insulin block-
ing reduces tumor incidence or progression and is re-
versible with re-introduction of insulin . Several of
the study findings conclude that hyperinsulinemia is an
independent risk factor from obesity and diabetes .
Insulin is a pleiotropic hormone with both mitogenic
and metabolic properties. It binds with the highest affin-
ity to its own receptor and with lower affinity to the
Robey Nutrition & Metabolism 2012, 9:72
Page 3 of 11
insulin growth factor-1 (IGF-1) receptor. The insulin re-
ceptor exists in two isoforms, IR-A and IR-B. IR-A is
expressed at lower levels than IR-B, but has greater
mitogenic activity when stimulated by insulin. Addition-
ally, both insulin receptor isoforms can form heterodi-
meric complexes with the IGF-1 receptor. The IR-A/IGF
hybrid receptor is expressed in all human tissues and
binds to insulin with high affinity . Activation of
these receptors by insulin stimulates cellular transform-
ation and promotes malignancy. Insulin promotes cellu-
lar proliferation, migration, and cellular survival mainly
through the MAPK pathway and sometimes through
PI3K pathway . It is proposed that chronically
exposed cells to even moderately elevated insulin levels
may favor cell proliferation and subsequently increase
the risk for malignant transformation . Thus, persist-
ent diet-induced acidosis favorable for maintaining
chronically high levels of cortisol could be supportive of
insulin sensitized tumor development.
Insulin growth factor
Studies examining the relationship between diet-induced
acidosis and insulin growth factor (IGF-1) levels have
varied outcomes. Acute induction of systemic acidosis
appears to reduce serum IGF-1 levels. Short-term (5-7
days) induction of metabolic acidosis in healthy male
subjects using ammonium chloride (NH4Cl) causes a
significant reduction in serum IGF-1 levels , con-
firming the results of an animal study carried out under
similar parameters . An adult fasting between 5-10
days induces a mild metabolic acidosis and appears to
have the effect of reducing plasma IGF-1 concentrations
as well [92-94]. Plasma IGF-1 levels are doubled by
treatment with bicarbonate in individuals with renal
tubular acidosis . In healthy subjects though,
neutralization of diet-induced acidosis with bicarbonate
treatment for a 7 day period does not have a significant
impact on IGF-1 levels .
High protein consumption over long-term periods
(months to years), which promotes greater net acid pro-
duction and subsequent latent or low-grade metabolic
acidosis, appears to have the opposite outcome from
short term studies on IGF-1 levels. Studies conducted
for 12 weeks or longer revealed a strong correlation be-
tween increased dietary protein and higher serum IGF-1
levels, suggesting at least long-term dietary habits, not
short-term perturbations, significantly impact IGF-1
serum concentrations [96-99]. Another epidemiological
study in healthy middle-aged and elderly male partici-
pants concluded that while protein consumption was
positively correlated to serum IGF-1 levels, the finding
was only consistent in individuals with a body mass
index (BMI) of <25kg/m2. There was no significant rela-
tionship between protein consumption and IGF-1 levels
in obese individuals (BMI >25kg/m2). The study also
reported that even while protein consumption increased
IGF-1 serum levels, there was an age dependent decline
in IGF-1 levels overall . The findings suggest a po-
tential for chronic acidogenic or ‘Western’ diets to ele-
vate IGF-1, but other factors complicate this dynamic
and require additional study. While it is reasonable to
predict that the individuals in these long-term studies
have developed low-grade acidosis from their diet, it
does not mean that acidosis is a driver of IGF-1 upregu-
lation. Furthermore, if diet-induced acidity upregulates
IGF-1, as suggested from the long-term dietary studies,
it is not yet determined if this occurs directly or indir-
ectly through cortisol signaling [2,88,89].
IGF-1 binding to the insulin receptor has been shown to
inhibit apoptosis and increase target cell proliferation,
thus linking its signaling activity to the risk of different
forms of cancer [101-103]. Several case control studies
have demonstrated a possible link between IGF-1 bio-
[104,105], colorectal [106-108], and breast . The
serum IGF-1concentrations in the case population of
the studies were relatively consistent with the ranges
measured in the previously discussed studies evaluating
the effects of ‘Western’ diet consumption on IGF-1
levels [97,100]. IGF-1 median levels of about 200ng/ml
in individuals younger than 70 years of age were typic-
ally associated with high protein diets (~90-105 g/day).
Leptin is an adipocyte derived hormone cytokine that
plays a role in regulating body weight and energy bal-
ance in the hypothalamus . Metabolic acidosis
modulates lipid metabolism in adipocytes [111-114].
Acidosis reduces leptin concentrations in cultured adi-
pocytes . In uraemic Wistar rats, sodium bicarbon-
ate supplementation appeared to increase (but not
significantly) leptin levels . A study in chronic kid-
ney disease (CKD) patients with metabolic acidosis
revealed that serum leptin was significantly increased by
treating patients with a daily low to moderate dose
(0.05-0.2g/kg) of sodium bicarbonate. The report con-
cluded that either reversal of acidosis increases serum
leptin or metabolic acidosis masks serum leptin levels
Studies comparing serum leptin between healthy indi-
viduals consuming acidogenic type diets and those con-
suming more alkaline types of diets present mixed and
variable findings. A study in men and women compared
serum leptin levels between a group of 279 people con-
suming a diet rich in fish and a group of 329 people
consuming a strictly vegetarian diet. Fish consumption is
a high net acid producing diet . Both groups had
Robey Nutrition & Metabolism 2012, 9:72
Page 4 of 11
similar BMI values. The study was consistent with find-
ings from in vitro, and animal investigations in that it
reported the protein-rich diet was associated with sig-
nificantly lower levels of serum leptin than in individuals
on the vegetarian diet, independent of age . How-
ever, another study measuring serum leptin levels in over
50,000 healthy participants reported a positive correl-
ation with consuming a ‘Western’ diet, at least in the 5th
quintile of the study population . Other studies
have not observed an independent association between
dietary intake and serum leptin levels after adjusting for
energy intake, gender, age and BMI [117,118]. These
reports illustrate the deep and complex relationship be-
tween acidogenic diets and serum leptin concentrations
Physiological acidosis may indirectly influence leptin ac-
tivity through cortisol signaling in obesity which is a con-
dition predicted to be associated with dysregulated acid-
base balance . As discussed previously, acid-base sta-
tus affects cortisol levels . In turn, cortisol stimulates
synthesis and secretion of leptin directly from adipocytes
. Plasma leptin concentrations are positively corre-
lated to body fat mass in humans [120,121]. Leptin has
been shown to negatively regulate cortisol levels in healthy
mice and humans [122-125], implicating leptin as an anti-
obesity factor. In humans, leptin attenuation of cortisol
appears to be a greater factor in females . Serum lep-
tin levels are paradoxically high, however, in obese indivi-
duals. This phenomenon is likely due to an acquired
leptin signaling resistance that eventually occurs in the
obese state . On average, plasma leptin concentra-
tions are 10 times higher in obese individuals compared to
those of lean individuals [127,128].
Elevated plasma leptin levels in obesity may contribute
to cancer incidence . Leptin has been implicated as a
functional component of mammary carcinoma in wild-
type p53 deficient mice . Epidemiological, animal,
and in vitro studies have demonstrated that leptin is asso-
ciated with breast cancer, prostate cancer, gynecological
cancers, gastrointestinal cancers, and leukemia [131-133].
Leptin has numerous molecular targets allowing for a
multifunctional effect. Leptin functions as a mitogen and
is known to stimulate breast tumor cells, prostate tumor
cell lines, as well as colonic and hepatic cells. Leptin sig-
naling is most likely to activate the mitogen-activated pro-
tein kinase (MAPK) pathway through binding of Ob-Rb
leptin receptor [131-138]. Leptin may also enhance cell
proliferation through protein kinase C alpha (PKC-α)
[139,140]. Leptin has been shown to bind the estrogen re-
ceptor and stimulate estrogen biosynthesis by induction of
aromatase activity [141,142]. Other cancer-permissive
functional activities of leptin include promotion of angio-
genesis [143-145], apoptosis , and cellular migration
Acid-base balance may play a role in modulating serum
levels of adipokine hormone adiponectin. Adiponectin
regulates multiple metabolic processes and is expressed
exclusively in mature adipocytes and circulates in the
plasma . Numerous human and animal studies have
reported a strong correlation between diet and serum
adiponectin levels. Higher levels of serum adiponectin
are typically associated with the ‘Mediterranean’ diet,
known for high vegetable and fruit intake and low or
moderate amounts of meat consumption. Other nutri-
tional factors such as the amount and type of fatty acid
intake are thought to influence serum adiponectin, but
the mechanisms of diet-induced regulation of adiponec-
tin regulation are not fully understood . The first
and only study demonstrating the role of acid-base dis-
equilibrium in regulating serum adiponectin concentra-
tions was an interventional trial to measure levels of
serum adiponectin in healthy individuals induced with
transient metabolic acidosis. Twenty healthy females
completed a seven day course of oral ammonium chlor-
ide (NH4Cl), resulting in reduced serum bicarbonate and
subsequent reduction in adiponectin mRNA and serum
protein adiponectin. This was further confirmed in cul-
tured adipocytes where acidosis inhibited gene transcrip-
tion of adiponectin, suggesting a pH sensing mechanism
at the cellular level may influence the regulation of adi-
ponectin production .
Low serum adiponectin levels are considered to be
permissive for development of cancer [3,150]. Reduced
serum adiponectin levels are observed in patients with
breast and gastric cancers, and simultaneously linked to
dietary lifestyle [151,152]. Higher serum adiponectin
may be protective against cancer as an anti-proliferative
through direct binding of other growth factors, such as
platelet derived growth factor-BB (PDGF-BB), heparin-
binding epidermal growth factor-like growth factor (HB-
EGF), and basic fibroblast growth factor (basic FGF),
hence restricting bioavailability . This was demon-
strated in a mouse study where adiponectin was shown
to slow tumor growth through its inhibitory effect on
tumor neovascularization .
In addition to its interference with proliferative signal-
ing, adiponectin mediates its regulatory effects through
two receptors, AdipoR1 and AdipoR2 . Signaling
through these receptors stimulates the activity of adeno-
sine monophosphate-activated protein (AMP-k) kinase
and peroxisome proliferator-activated receptor alpha
(PPARα) which drives glucose uptake and fatty acid oxi-
dation. Through this mechanism, coupled with AdipoR1
receptor association with the insulin receptor, adiponec-
tin is proposed to enhance signal transduction to
promote insulin sensitivity . Although a greater
understanding is necessary, there is evidence suggesting
Robey Nutrition & Metabolism 2012, 9:72
Page 5 of 11
acid-base status maintained through dietary intake could
promote carcinogenesis or tumor progression through
dysregulated adiponectin signaling.
A very recent discussion about the role of diet-induced
acidosis and pathophysiology introduces the hypothesis
that persistent acidogenic or ‘Western’ diets lead to la-
tent or low-grade metabolic acidosis, subsequent acid-
base balance disequilibrium, and production of lactic
acid at the cellular level. These events appear to be crit-
ical upstream precursors to a host of ill-conditions, dis-
eases, and ageing. The premise further explains that
increased [H+] accumulates persistently in the mito-
chondrial matrix without contributing to ATP produc-
tion. This dynamic is theorized to inhibit mitochondrial
energy production (MEP) through inhibition of the TCA
cycle. MEP inhibition results in the diversion of elec-
trons away from completion of the electron transport
chain and toward the reduction of oxygen (O2) into re-
active oxygen species (ROS) such as free radical oxygen
species or peroxides [34,157]. As this cycle continues,
vulnerable cells develop a reduced capacity to restore
homeostatic balance and are subject to increased intra-
cellular oxidative stress.
The oxidative stress generated by ROS has multiple
effects causing damage to cellular and organelle mem-
branes, sulphydryl groups in proteins, and cross-linking
or fragmenting ribonucleoproteins and DNA. DNA mu-
tagenesis through persistent oxidative stress is generally
accepted as a major mechanism behind carcinogenesis
and cancer progression . Oxidative DNA damage
has been associated with breast cancer [159,160], hepa-
tocellular carcinoma and liver cancer [161,162], and
prostate cancer [163-165]. Oxidative stress in correlation
with obesity can manifest and have significant patho-
genic effects within the first two decades of life .
Although oxidative stress can be measured directly and
indirectly through various methods, it is far more diffi-
cult to differentiate between acidogenic diet-induced and
endogenous ROS production coupled with antioxidant
status and other molecular factors that may impact oxi-
dative steady state .
Although not fully understood, the long-term effect of
diet-induced acidosis is considered to have an impact on
bone osteoclasts . Serum [HCO3
may only partially account for neutralization of acidity,
and may be supplemented further by alkaline stores
from the soft tissue and bone . Osteoclastic resorp-
tion of minerals is a proposed mechanism in buffering
systemic acidosis [169,170]. In vitro findings demonstrat-
ing the mechanisms of excess [H+] on bone tissue is the
most reliable evidence currently driving the concept of
compensatory buffering through acidosis-induced bone
resorption. In cultured osteoclasts, lower pH conditions
induce the breaking up of mineralized bone tissue
matrix [171-175]. Bicarbonate [HCO3
sufficient to acidify media and promote net [H+] influx
into bone , and appears to be necessary (not just
reduced pH conditions which could be induced by re-
spiratory acidosis) to stimulate calcium [Ca2
Stimulation of osteoclastic resorption by diet-induced
acidosis is mediated through receptor activator of NFкB
ligand (RANKL) signaling . RANKL signaling is
known to promote osteoclast differentiation and acti-
vates various mitogenic pathways that are frequently
operational in tumor cells, including p38, MAPK, AP-1,
c-Jun, and Akt/PKB [179-182]. RANKL expression has
also been observed in lymphoid tissue, skeletal muscle,
thymus, liver, colon, intestine, heart, brain, and the ad-
renal and mammary glands . RANKL signaling has
been shown in mouse models to promote tumorigenesis
in breast and lung tissue . It is unknown, however,
if systemic acidosis induces RANKL activity in other cell
types besides osteoclasts.
One of the strongest RANK-stimulated transcription
factors in osteoclasts is the nuclear factor of activated
T-cells (NFATc1) protein [185,186]. Once exposed to
extracellular acidic pH, cytosolic [Ca2
clasts increase intracellular localization of nuclear tran-
scription factor NFATc1 through calcineurin signaling.
The ovarian cancer G-protein coupled proton-sensing
receptor (OGR1), which is induced during osteoclast
differentiation, is thought of as the primary mediator
between acidosis and NFATc1 activation. Calcineurin
signaling is not required however, to maintain NFATc1
activation under extracellular acidic conditions and
NFATc1 activity is reversed by extracellular alkaline
conditions, suggesting that acidosis directly prevents
NFATc1 inactivation by kinases . NFATc1 has
many functions in cancer  and has been linked to
regulation of the c-Myc oncogene [189-193]. Although
the link between acidosis and RANK/NFATc1 mediated
carcinogenesis or tumor promotion is not established,
chronic activation of these factors through a dietary
induced state of dysregulated acid-base status may con-
tribute to cancer risk.
-] deficiency may be
+] efflux from
+] stores in osteo-
This work examines the potential for cancer risk or
tumor promoting consequences of diet-induced acidosis.
Although protein is a major factor involved in promot-
ing endogenous acid production, it should be made clear
that attenuation of protein consumption is not a recom-
mended dietary strategy for attaining improved acid-
Robey Nutrition & Metabolism 2012, 9:72
Page 6 of 11
base balance. There is scientific evidence supporting the
concept that appropriate alkali supplementation in the
form of fruits and vegetables serves aptly to neutralize
excess [H+] produced from protein metabolism [34,194].
The analysis provided discusses how diet-induced acid-
osis is a potential upstream and indirect trigger in a
multifactorial cascade of molecular events associated
with carcinogenesis. There is limited evidence to sug-
gest that dietary acidosis alone is sufficient in increas-
ing cancer risk, but it may function in concert with
other factors associated with cancer risk. Obesity or
metabolic syndrome, which effect glucocorticoid and
adipokine profiles and are often linked to insulin re-
sistance and the pro-inflammatory state, could also
serve as significant factors as they are associated with
both acidogenic or ‘Western’ diet  and cancer risk
In conclusion, there are numerous systemic pathways
affected by diet-induced acidosis that may be cancer
promoting, but a causal role is poorly defined. Moreover,
the contribution of diet-induced acidosis in driving car-
cinogenesis would be difficult to measure especially
since the effects appear to accumulate for a long period
of time. Nonetheless, exploring the role of dietary
induced acidosis involvement in molecular pathways
that promote carcinogenesis will raise new questions
and foster ideas to improve our understanding on the
role of acid-base balance in human disease.
IGF-1: Insulin growth factor; GLUT: Glucose transporter; IDO: Indoleamine 2,3-
dioxygenase; TDO: 2,3-dioxygenase; APC: Antigen presenting cell; AHR: Aryl
hydrocarbon receptor; ROS: Reactive oxygen species; CKD: Chronic kidney
disease; BMI: Body mass index; PDGF-BB: Platelet derived growth factor-BB;
OGR1: Ovarian cancer G-protein coupled proton-sensing receptor;
NFATc1: Nuclear factor of activated T-cells; AMP-k: Adenosine
monophosphate-activated protein kinase; PPARa: Peroxisome proliferator-
activated receptor alpha; MEP: Mitochondrial energy production;
MAPK: Mitogen-activated protein kinase; 11ßHSD2: 11ß-hydroxysteroid
dehydrogenase 2; HB EGF: Heparin-binding epidermal growth factor-like
growth factor; RANKL: Receptor activator of NFкB ligand; OGR1: Ovarian
cancer G-protein coupled proton-sensing receptor; NFATc1: Nuclear factor of
activated T-cells; AMP-k: Adenosine monophosphate-activated protein kinase;
PPARa: Peroxisome proliferator-activated receptor alpha; MEP: Mitochondrial
energy production; MAPK: Mitogen-activated protein kinase; 11ßHSD2: 11ß-
hydroxysteroid dehydrogenase 2; AICR: American Institute for Cancer
The author declares that he has no competing interests.
IR conceived and drafted the manuscript in its entirety and approves the
National Centers for Complementary and Alternative Medicine, NIH grant
Received: 24 April 2012 Accepted: 27 July 2012
Published: 1 August 2012
Cancer Facts and Figures. In American Cancer Society. Edited by Society AC.
Atlanta:; 2004. http://www.cancer.org/acs/groups/content/
2.Calle EE, Kaaks R: Overweight, obesity and cancer: epidemiological
evidence and proposed mechanisms. Nat Rev Cancer 2004, 4(8):579–591.
3.Hursting SD, Berger NA: Energy balance, host-related factors, and cancer
progression. J Clin Oncol 2010, 28(26):4058–4065.
4.Research WCRFAIfC: Food, Nutrition, and Physical Activity, and the Prevention
of Cancer: A Global Perspective. In. Washington DC: AICR; 2007.
5.Kato Y, Lambert CA, Colige AC, Mineur P, Noel A, Frankenne F, Foidart JM,
Baba M, Hata R, Miyazaki K, et al: Acidic extracellular pH induces matrix
metalloproteinase-9 expression in mouse metastatic melanoma cells
through the phospholipase D-mitogen-activated protein kinase
signaling. J Biol Chem 2005, 280(12):10938–10944.
6.Kato Y, Ozawa S, Tsukuda M, Kubota E, Miyazaki K, St-Pierre Y, Hata R: Acidic
extracellular pH increases calcium influx-triggered phospholipase D
activity along with acidic sphingomyelinase activation to induce matrix
metalloproteinase-9 expression in mouse metastatic melanoma.
FEBS J 2007, 274(12):3171–3183.
7. Martinez-Zaguilan R, Seftor EA, Seftor RE, Chu YW, Gillies RJ, Hendrix MJ:
Acidic pH enhances the invasive behavior of human melanoma cells.
Clin Exp Metastasis 1996, 14(2):176–186.
8.Moellering RE, Black KC, Krishnamurty C, Baggett BK, Stafford P, Rain M,
Gatenby RA, Gillies RJ: Acid treatment of melanoma cells selects for
invasive phenotypes. Clin Exp Metastasis 2008, 25(4):411–425.
9. Rofstad EK, Mathiesen B, Kindem K, Galappathi K: Acidic extracellular pH
promotes experimental metastasis of human melanoma cells in athymic
nude mice. Cancer Res 2006, 66(13):6699–6707.
10. Rozhin J, Sameni M, Ziegler G, Sloane BF: Pericellular pH affects
distribution and secretion of cathepsin B in malignant cells.
Cancer Res 1994, 54(24):6517–6525.
11.Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, Xie K: Regulation of
vascular endothelial growth factor expression by acidosis in human
cancer cells. Oncogene 2001, 20(28):3751–3756.
12. Welbourne TC, Francoeur D: Influence of aldosterone on renal ammonia
production. Am J Physiol 1977, 233(1):E56–E60.
13. Xu L, Fidler IJ: Acidic pH-induced elevation in interleukin 8 expression by
human ovarian carcinoma cells. Cancer Res 2000, 60(16):4610–4616.
14.Xu L, Fukumura D, Jain RK: Acidic extracellular pH induces vascular
endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2
MAPK signaling pathway: mechanism of low pH-induced VEGF.
J Biol Chem 2002, 277(13):11368–11374.
15.Schornack PA, Gillies RJ: Contributions of cell metabolism and
H+diffusion to the acidic pH of tumors. Neoplasia 2003, 5(2):135–145.
16.Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH,
Brand-Miller J: Origins and evolution of the Western diet: health
implications for the 21st century. Am J Clin Nutr 2005, 81(2):341–354.
17.Halperin ML: Metabolism and acid-base physiology. Artif Organs 1982,
18. Kleinman J, Lemann J Jr: Acid Production. In Clinical disorders of fluid and
electrolyte metabolism. 4th edition. Edited by Maxwell M, Kleeman C, Narins R.
New York: McGraw Hill; 1987:159–173.
19.Frassetto LA, Morris RC Jr, Sebastian A: Dietary sodium chloride intake
independently predicts the degree of hyperchloremic metabolic acidosis
in healthy humans consuming a net acid-producing diet.
Am J Physiol Renal Physiol 2007, 293(2):F521–F525.
20. Frings-Meuthen P, Baecker N, Heer M: Low-grade metabolic acidosis may
be the cause of sodium chloride-induced exaggerated bone resorption.
J Bone Miner Res 2008, 23(4):517–524.
21. Frassetto LA, Todd KM, Morris RC Jr, Sebastian A: Estimation of net
endogenous noncarbonic acid production in humans from diet
potassium and protein contents. Am J Clin Nutr 1998, 68(3):576–583.
22.Remer T, Manz F: Paleolithic diet, sweet potato eaters, and potential renal
acid load. Am J Clin Nutr 2003, 78(4):802–803. author reply 803-804.
23. Remer T, Manz F: Estimation of the renal net acid excretion by adults
consuming diets containing variable amounts of protein. Am J Clin Nutr
24. Remer T, Manz F: Dietary protein as a modulator of the renal net acid
excretion capacity: Evidence that an increased protein intake improves
Robey Nutrition & Metabolism 2012, 9:72
Page 7 of 11
the capability of the kidney to excrete ammonium. J Nutr Biochem 1995,
Frassetto L, Morris RC Jr: Sellmeyer DE, Todd K, Sebastian A: Diet,
evolution and aging–the pathophysiologic effects of the post-
agricultural inversion of the potassium-to-sodium and base-to-chloride
ratios in the human diet. Eur J Nutr 2001, 40(5):200–213.
Frassetto L, Sebastian A: Age and systemic acid-base equilibrium: analysis
of published data. J Gerontol A Biol Sci Med Sci 1996, 51(1):B91–B99.
Frassetto LA, Morris RC Jr, Sebastian A: Effect of age on blood acid-base
composition in adult humans: role of age-related renal functional
decline. Am J Physiol 1996, 271(6 Pt 2):F1114–F1122.
Pizzorno J, Frassetto LA, Katzinger J: Diet-induced acidosis: is it real and
clinically relevant? Br J Nutr 2010, 103(8):1185–1194.
Kurtz I, Maher T, Hulter HN, Schambelan M, Sebastian A: Effect of diet on
plasma acid-base composition in normal humans. Kidney Int 1983,
Sebastian A, Frassetto LA, Sellmeyer DE, Merriam RL, Morris RC Jr:
Estimation of the net acid load of the diet of ancestral preagricultural
Homo sapiens and their hominid ancestors. Am J Clin Nutr 2002,
Vormann J, Goedeke T: Latent acidosis: acidity as a cause for chronic
diseases [Latente Azidose: Übersäuerung als Ursache chronischer
Erkrankungen]. Schewiz Zschr Ganszheits Medizin 2002, 2:90–96.
Gluck SL: Acid-base. Lancet 1998, 352(9126):474–479.
Kraut JA, Madias NE: Metabolic acidosis: pathophysiology, diagnosis and
management. Nat Rev Nephrol 2010, 6(5):274–285.
Berkemeyer S: Acid-base balance and weight gain: are there crucial links
via protein and organic acids in understanding obesity? Med Hypotheses
Hwang JJ, Curthoys NP: Effect of acute alterations in acid-base balance
on rat renal glutaminase and phosphoenolpyruvate carboxykinase gene
expression. J Biol Chem 1991, 266(15):9392–9396.
Karim Z, Attmane-Elakeb A, Bichara M: Renal handling of NH4+ in relation
to the control of acid-base balance by the kidney. J Nephrol 2002,
Welbourne TC: Acidosis activation of the pituitary-adrenal-renal
glutaminase I axis. Endocrinology 1976, 99(4):1071–1079.
Espino L, Suarez ML, Santamarina G, Goicoa A, Fidalgo LE: Effects of dietary
cation-anion difference on blood cortisol and ACTH levels in
reproducing ewes. J Vet Med A Physiol Pathol Clin Med 2005, 52(1):8–12.
Gibson EL, Checkley S, Papadopoulos A, Poon L, Daley S, Wardle J:
Increased salivary cortisol reliably induced by a protein-rich midday
meal. Psychosom Med 1999, 61(2):214–224.
Slag MF, Ahmad M, Gannon MC, Nuttall FQ: Meal stimulation of cortisol
secretion: a protein induced effect. Metabolism 1981, 30(11):1104–1108.
Maurer M, Riesen W, Muser J, Hulter HN, Krapf R: Neutralization of Western
diet inhibits bone resorption independently of K intake and reduces
cortisol secretion in humans. Am J Physiol Renal Physiol 2003,
Lemmens SG, Born JM, Martens EA, Martens MJ, Westerterp-Plantenga MS:
Influence of consumption of a high-protein vs. high-carbohydrate meal
on the physiological cortisol and psychological mood response in men
and women. PLoS One 2011, 6(2):e16826.
Martens MJ, Rutters F, Lemmens SG, Born JM, Westerterp-Plantenga MS:
Effects of single macronutrients on serum cortisol concentrations in
normal weight men. Physiol Behav 2010, 101(5):563–567.
Vicennati V, Ceroni L, Gagliardi L, Gambineri A, Pasquali R: Comment:
response of the hypothalamic-pituitary-adrenocortical axis to high-
protein/fat and high-carbohydrate meals in women with different
obesity phenotypes. J Clin Endocrinol Metab 2002, 87(8):3984–3988.
Zhao XY, Malloy PJ, Krishnan AV, Swami S, Navone NM, Peehl DM, Feldman D:
Glucocorticoids can promote androgen-independent growth of prostate
cancer cells through a mutated androgen receptor.
Nat Med 2000, 6(6):703–706.
Goya L, Maiyar AC, Ge Y, Firestone GL: Glucocorticoids induce a G1/G0 cell
cycle arrest of Con8 rat mammary tumor cells that is synchronously
reversed by steroid withdrawal or addition of transforming growth
factor-alpha. Mol Endocrinol 1993, 7(9):1121–1132.
Lippman M, Bolan G, Huff K: The effects of glucocorticoids and
progesterone on hormone-responsive human breast cancer in long-term
tissue culture. Cancer Res 1976, 36(12):4602–4609.
48.Wan Y, Nordeen SK: Overlapping but distinct gene regulation profiles by
glucocorticoids and progestins in human breast cancer cells.
Mol Endocrinol 2002, 16(6):1204–1214.
Guyre PM, Girard MT, Morganelli PM, Manganiello PD: Glucocorticoid
effects on the production and actions of immune cytokines.
J Steroid Biochem 1988, 30(1–6):89–93.
Oxenkrug GF: Genetic and hormonal regulation of tryptophan
kynurenine metabolism: implications for vascular cognitive impairment,
major depressive disorder, and aging. Ann N Y Acad Sci 2007, 1122:35–49.
Katz JB, Muller AJ, Prendergast GC: Indoleamine 2,3-dioxygenase in T-cell
tolerance and tumoral immune escape. Immunol Rev 2008, 222:206–221.
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S,
Schumacher T, Jestaedt L, Schrenk D, Weller M, et al: An endogenous
tumour-promoting ligand of the human aryl hydrocarbon receptor.
Nature 2011, 478(7368):197–203.
Prendergast GC, Metz R, Muller AJ: Towards a genetic definition of cancer-
associated inflammation: role of the IDO pathway. Am J Pathol 2011,
Fallarino F, Gizzi S, Mosci P, Grohmann U, Puccetti P: Tryptophan
catabolism in IDO+plasmacytoid dendritic cells. Curr Drug Metab 2007,
Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, Burns EJ, Sherr DH,
Weiner HL, Kuchroo VK: The aryl hydrocarbon receptor interacts with c-
Maf to promote the differentiation of type 1 regulatory T cells induced
by IL-27. Nat Immunol 2010, 11(9):854–861.
Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M,
Oukka M, Weiner HL: Control of T(reg) and T(H)17 cell differentiation by
the aryl hydrocarbon receptor. Nature 2008, 453(7191):65–71.
Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM, Burns EJ,
Weiner HL: An endogenous aryl hydrocarbon receptor ligand acts on
dendritic cells and T cells to suppress experimental autoimmune
encephalomyelitis. Proc Natl Acad Sci U S A 2010, 107(48):20768–20773.
Miller LK, Kral JG, Strain GW, Zumoff B: Differential binding of
dexamethasone to ammonium sulfate precipitates of human adipose
tissue cytosols. Steroids 1987, 49(6):507–522.
Rebuffe-Scrive M, Bronnegard M, Nilsson A, Eldh J, Gustafsson JA, Bjorntorp P:
Steroid hormone receptors in human adipose tissues. J Clin Endocrinol
Metab 1990, 71(5):1215–1219.
Bujalska IJ, Kumar S, Stewart PM: Does central obesity reflect “Cushing's
disease of the omentum"? Lancet 1997, 349(9060):1210–1213.
Buren J, Liu HX, Jensen J, Eriksson JW: Dexamethasone impairs insulin
signalling and glucose transport by depletion of insulin receptor
substrate-1, phosphatidylinositol 3-kinase and protein kinase B in
primary cultured rat adipocytes. Eur J Endocrinol 2002, 146(3):419–429.
Carter-Su C, Okamoto K: Effect of glucocorticoids on hexose transport in
rat adipocytes. Evidence for decreased transporters in the plasma
membrane. J Biol Chem 1985, 260(20):11091–11098.
Fried SK, Russell CD, Grauso NL, Brolin RE: Lipoprotein lipase regulation by
insulin and glucocorticoid in subcutaneous and omental adipose tissues
of obese women and men. J Clin Invest 1993, 92(5):2191–2198.
Livingston JN, Lockwood DH: Effect of glucocorticoids on the glucose
transport system of isolated fat cells. J Biol Chem 1975,
Sakoda H, Ogihara T, Anai M, Funaki M, Inukai K, Katagiri H, Fukushima Y,
Onishi Y, Ono H, Fujishiro M, et al: Dexamethasone-induced insulin
resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport
rather than insulin signal transduction. Diabetes 2000, 49(10):1700–1708.
Turnbow MA, Smith LK, Garner CW: The oxazolidinedione CP-92,768-2
partially protects insulin receptor substrate-1 from dexamethasone down-
regulation in 3T3-L1 adipocytes. Endocrinology 1995, 136(4):1450–1458.
Frayn KN: Adipose tissue and the insulin resistance syndrome.
Proc Nutr Soc 2001, 60(3):375–380.
Andrews RC, Walker BR: Glucocorticoids and insulin resistance: old
hormones, new targets. Clin Sci (Lond) 1999, 96(5):513–523.
Qi D, Rodrigues B: Glucocorticoids produce whole body insulin resistance
with changes in cardiac metabolism. Am J Physiol Endocrinol Metab 2007,
Reynolds RM, Walker BR: Human insulin resistance: the role of
glucocorticoids. Diabetes Obes Metab 2003, 5(1):5–12.
Everhart J, Wright D: Diabetes mellitus as a risk factor for pancreatic
cancer. A meta-analysis. JAMA 1995, 273(20):1605–1609.
Robey Nutrition & Metabolism 2012, 9:72
Page 8 of 11
72.Fair AM, Dai Q, Shu XO, Matthews CE, Yu H, Jin F, Gao YT, Zheng W: Energy
balance, insulin resistance biomarkers, and breast cancer risk.
Cancer Detect Prev 2007, 31(3):214–219.
Giovannucci E: Insulin and colon cancer. Cancer Causes Control 1995,
McKeown-Eyssen G: Epidemiology of colorectal cancer revisited: are
serum triglycerides and/or plasma glucose associated with risk?
Cancer Epidemiol Biomarkers Prev 1994, 3(8):687–695.
Pisani P: Hyper-insulinaemia and cancer, meta-analyses of
epidemiological studies. Arch Physiol Biochem 2008, 114(1):63–70.
Weiderpass E, Partanen T, Kaaks R, Vainio H, Porta M, Kauppinen T, Ojajarvi A,
Boffetta P, Malats N: Occurrence, trends and environment etiology of
pancreatic cancer. Scand J Work Environ Health 1998, 24(3):165–174.
Kaaks R, Lukanova A, Kurzer MS: Obesity, endogenous hormones, and
endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers
Prev 2002, 11(12):1531–1543.
Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S,
Borch-Johnsen K, Olsen JH: Cancer incidence in a population-based
cohort of patients hospitalized with diabetes mellitus in Denmark.
J Natl Cancer Inst 1997, 89(18):1360–1365.
Kaaks R: Nutrition, hormones, and breast cancer: is insulin the missing
link? Cancer Causes Control 1996, 7(6):605–625.
Stoll BA: Western nutrition and the insulin resistance syndrome: a link to
breast cancer. Eur J Clin Nutr 1999, 53(2):83–87.
Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J,
Ho GY, Xue X, Anderson GL, et al: Insulin, insulin-like growth factor-I, and risk
of breast cancer in postmenopausal women. J Natl Cancer Inst 2009,
Irwin ML, Duggan C, Wang CY, Smith AW, McTiernan A, Baumgartner RN,
Baumgartner KB, Bernstein L, Ballard-Barbash R: Fasting C-peptide levels
and death resulting from all causes and breast cancer: the health,
eating, activity, and lifestyle study. J Clin Oncol 2011, 29(1):47–53.
Kabat GC, Kim M, Caan BJ, Chlebowski RT, Gunter MJ, Ho GY, Rodriguez BL,
Shikany JM, Strickler HD, Vitolins MZ, et al: Repeated measures of serum
glucose and insulin in relation to postmenopausal breast cancer.
Int J Cancer 2009, 125(11):2704–2710.
Tran TT, Medline A, Bruce WR: Insulin promotion of colon tumors in rats.
Cancer Epidemiol Biomarkers Prev 1996, 5(12):1013–1015.
Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D: Insulin-sensitizing
therapy attenuates type 2 diabetes-mediated mammary tumor
progression. Diabetes 2010, 59(3):686–693.
Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y,
Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, et al: Insulin-
mediated acceleration of breast cancer development and progression
in a nonobese model of type 2 diabetes. Cancer Res 2010, 70(2):
Heuson JC, Legros N: Influence of insulin deprivation on growth of the
7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats
subjected to alloxan diabetes and food restriction. Cancer Res 1972,
Belfiore A, Malaguarnera R: Insulin receptor and cancer. Endocr Relat
Cancer 2011, 18(4):R125–R147.
Vigneri P, Frasca F, Sciacca L, Frittitta L, Vigneri R: Obesity and cancer.
Nutr Metab Cardiovasc Dis 2006, 16(1):1–7.
Brungger M, Hulter HN, Krapf R: Effect of chronic metabolic acidosis on
thyroid hormone homeostasis in humans. Am J Physiol 1997,
272(5 Pt 2):F648–F653.
Challa A, Chan W, Krieg RJ Jr, Thabet MA, Liu F, Hintz RL, Chan JC: Effect of
metabolic acidosis on the expression of insulin-like growth factor and
growth hormone receptor. Kidney Int 1993, 44(6):1224–1227.
Clemmons DR, Klibanski A, Underwood LE, McArthur JW, Ridgway EC, Beitins
IZ, Van Wyk JJ: Reduction of plasma immunoreactive somatomedin C
during fasting in humans. J Clin Endocrinol Metab 1981, 53(6):1247–1250.
Isley WL, Underwood LE, Clemmons DR: Dietary components that regulate
serum somatomedin-C concentrations in humans. J Clin Invest 1983,
Isley WL, Underwood LE, Clemmons DR: Changes in plasma
somatomedin-C in response to ingestion of diets with variable protein
and energy content. JPEN J Parenter Enteral Nutr 1984, 8(4):407–411.
Caldas A, Fontoura M: Effects of chronic metabolic acidosis (CMA) in
24-hour growth hormone secretion. J Am Soc Nephrol 1993, 4:828–828.
96.Cadogan J, Eastell R, Jones N, Barker ME: Milk intake and bone mineral
acquisition in adolescent girls: randomised, controlled intervention trial.
BMJ 1997, 315(7118):1255–1260.
Fontana L, Klein S, Holloszy JO: Long-term low-protein, low-calorie diet
and endurance exercise modulate metabolic factors associated with
cancer risk. Am J Clin Nutr 2006, 84(6):1456–1462.
Heaney RP, McCarron DA, Dawson-Hughes B, Oparil S, Berga SL, Stern JS,
Barr SI, Rosen CJ: Dietary changes favorably affect bone remodeling in
older adults. J Am Diet Assoc 1999, 99(10):1228–1233.
Schurch MA, Rizzoli R, Slosman D, Vadas L, Vergnaud P, Bonjour JP: Protein
supplements increase serum insulin-like growth factor-I levels and
attenuate proximal femur bone loss in patients with recent hip fracture.
A randomized, double-blind, placebo-controlled trial. Ann Intern Med
100. Giovannucci E, Pollak M, Liu Y, Platz EA, Majeed N, Rimm EB, Willett WC:
Nutritional predictors of insulin-like growth factor I and their
relationships to cancer in men. Cancer Epidemiol Biomarkers Prev 2003,
101. Cohen P, Peehl DM, Rosenfeld RG: The IGF axis in the prostate.
Horm Metab Res 1994, 26(2):81–84.
102. LeRoith D, Baserga R, Helman L, Roberts CT Jr: Insulin-like growth factors
and cancer. Ann Intern Med 1995, 122(1):54–59.
103. Pollak MN: Endocrine effects of IGF-I on normal and transformed breast
epithelial cells: potential relevance to strategies for breast cancer
treatment and prevention. Breast Cancer Res Treat 1998, 47(3):209–217.
104. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P,
Hennekens CH, Pollak M: Plasma insulin-like growth factor-I and prostate
cancer risk: a prospective study. Science 1998, 279(5350):563–566.
105. Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO:
Insulin-like growth factor 1 in relation to prostate cancer and benign
prostatic hyperplasia. Br J Cancer 1997, 76(9):1115–1118.
106. Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H,
Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E: Serum C-peptide,
insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal
cancer risk in women. J Natl Cancer Inst 2000, 92(19):1592–1600.
107. Ma J, Giovannucci E, Pollak M, Chan JM, Gaziano JM, Willett W, Stampfer MJ:
Milk intake, circulating levels of insulin-like growth factor-I, and risk of
colorectal cancer in men. J Natl Cancer Inst 2001, 93(17):1330–1336.
108. Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ:
Prospective study of colorectal cancer risk in men and plasma levels of
insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst
109. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B,
Speizer FE, Pollak M: Circulating concentrations of insulin-like growth factor-I
and risk of breast cancer. Lancet 1998, 351(9113):1393–1396.
110. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM:
Positional cloning of the mouse obese gene and its human homologue.
Nature 1994, 372(6505):425–432.
111. Disthabanchong S, Niticharoenpong K, Radinahamed P, Stitchantrakul W,
Ongphiphadhanakul B, Hongeng S: Metabolic acidosis lowers circulating
adiponectin through inhibition of adiponectin gene transcription.
Nephrol Dial Transplant 2010, 26(2):592–598.
112. Teta D, Bevington A, Brown J, Pawluczyk I, Harris K, Walls J: Acidosis
downregulates leptin production from cultured adipocytes through a
glucose transport-dependent post-transcriptional mechanism.
J Am Soc Nephrol 2003, 14(9):2248–2254.
113. Teta D, Bevington A, Brown J, Throssell D, Harris KP, Walls J: Effects of
acidosis on leptin secretion from 3T3-L1 adipocytes and on serum leptin
in the uraemic rat. Clin Sci (Lond) 1999, 97(3):363–368.
114. Zheng F, Qiu X, Yin S, Li Y: Changes in serum leptin levels in chronic renal
failure patients with metabolic acidosis. J Ren Nutr 2001, 11(4):207–211.
115. Winnicki M, Somers VK, Accurso V, Phillips BG, Puato M, Palatini P, Pauletto
P: Fish-rich diet, leptin, and body mass. Circulation 2002, 106(3):289–291.
116. Fung TT, Rimm EB, Spiegelman D, Rifai N, Tofler GH, Willett WC, Hu FB:
Association between dietary patterns and plasma biomarkers of
obesity and cardiovascular disease risk. Am J Clin Nutr 2001,
117. Chu NF, Stampfer MJ, Spiegelman D, Rifai N, Hotamisligil GS, Rimm EB:
Dietary and lifestyle factors in relation to plasma leptin concentrations
among normal weight and overweight men. Int J Obes Relat Metab Disord
Robey Nutrition & Metabolism 2012, 9:72
Page 9 of 11
118. Ganji V, Kafai MR, McCarthy E: Serum leptin concentrations are not related
to dietary patterns but are related to sex, age, body mass index, serum
triacylglycerol, serum insulin, and plasma glucose in the US population.
Nutr Metab (Lond) 2009, 6:3.
119. Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J,
Bue-Valleskey J, Stephens TW: Regulation of expression of ob mRNA
and protein by glucocorticoids and cAMP. J Biol Chem 1996,
120. Girard J: Is leptin the link between obesity and insulin resistance?
Diabetes Metab 1997, 23(Suppl 3):16–24.
121. Kahn BB, Flier JS: Obesity and insulin resistance. J Clin Invest 2000, 106
122. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS: Leptin
inhibition of the hypothalamic-pituitary-adrenal axis in response to
stress. Endocrinology 1997, 138(9):3859–3863.
123. Korbonits M, Trainer PJ, Little JA, Edwards R, Kopelman PG, Besser GM, Svec F,
Grossman AB: Leptin levels do not change acutely with food administration
in normal or obese subjects, but are negatively correlated with pituitary-
adrenal activity. Clin Endocrinol (Oxf) 1997, 46(6):751–757.
124. Remer T, Dimitriou T, Maser-Gluth C: Renal net acid excretion and plasma
leptin are associated with potentially bioactive free glucocorticoids in
healthy lean women. J Nutr 2008, 138(2):426S–430S.
125. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L,
Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, et al: The role of
neuropeptide Y in the antiobesity action of the obese gene product.
Nature 1995, 377(6549):530–532.
126. Enriori PJ, Evans AE, Sinnayah P, Cowley MA: Leptin resistance and obesity.
Obesity (Silver Spring) 2006, 14(Suppl 5):254S–258S.
127. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR,
Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al: Serum
immunoreactive-leptin concentrations in normal-weight and obese
humans. N Engl J Med 1996, 334(5):292–295.
128. Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ: Plasma
resistin, adiponectin and leptin levels in lean and obese subjects:
correlations with insulin resistance. Eur J Endocrinol 2003, 149(4):331–335.
129. Garofalo C, Surmacz E: Leptin and cancer. J Cell Physiol 2006, 207(1):12–22.
130. Hursting SD, Perkins SN, Phang JM, Barrett JC: Diet and cancer prevention
studies in p53-deficient mice. J Nutr 2001, 131(11 Suppl):3092S–3094S.
131. Rose DP, Komninou D, Stephenson GD: Obesity, adipocytokines, and
insulin resistance in breast cancer. Obes Rev 2004, 5(3):153–165.
132. Somasundar P, Frankenberry KA, Skinner H, Vedula G, McFadden DW, Riggs D,
Jackson B, Vangilder R, Hileman SM, Vona-Davis LC: Prostate cancer cell
proliferation is influenced by leptin. J Surg Res 2004, 118(1):71–82.
133. Somasundar P, McFadden DW, Hileman SM, Vona-Davis L: Leptin is a
growth factor in cancer. J Surg Res 2004, 116(2):337–349.
134. Dieudonne MN, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R,
Giudicelli Y: Leptin mediates a proliferative response in human MCF7 breast
cancer cells. Biochem Biophys Res Commun 2002, 293(1):622–628.
135. Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ,
Peppelenbosch MP: Leptin is a growth factor for colonic epithelial cells.
Gastroenterology 2001, 121(1):79–90.
136. Hu X, Juneja SC, Maihle NJ, Cleary MP: Leptin–a growth factor in normal
and malignant breast cells and for normal mammary gland
development. J Natl Cancer Inst 2002, 94(22):1704–1711.
137. Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J: Identification of leptin
receptors in human breast cancer: functional activity in the T47-D breast
cancer cell line. Mol Cell Endocrinol 2002, 188(1–2):219–226.
138. Wang Y, Kuropatwinski KK, White DW, Hawley TS, Hawley RG, Tartaglia LA,
Baumann H: Leptin receptor action in hepatic cells. J Biol Chem 1997,
139. Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M,
Cooper DR, Yasuda K: Leptin and high glucose stimulate cell proliferation
in MCF-7 human breast cancer cells: reciprocal involvement of PKC-
alpha and PPAR expression. Biochim Biophys Acta 2002, 1592(2):107–116.
140. Takekoshi K, Ishii K, Nanmoku T, Shibuya S, Kawakami Y, Isobe K, Nakai T:
Leptin stimulates catecholamine synthesis in a PKC-dependent manner
in cultured porcine adrenal medullary chromaffin cells. Endocrinology
141. Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, Ando S:
Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell
line. J Biol Chem 2003, 278(31):28668–28676.
142. Catalano S, Mauro L, Marsico S, Giordano C, Rizza P, Rago V, Montanaro D,
Maggiolini M, Panno ML, Ando S: Leptin induces, via ERK1/ERK2 signal,
functional activation of estrogen receptor alpha in MCF-7 cells. J Biol
Chem 2004, 279(19):19908–19915.
143. Bouloumie A, Drexler HC, Lafontan M, Busse R: Leptin, the product of Ob
gene, promotes angiogenesis. Circ Res 1998, 83(10):1059–1066.
144. Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, Jang Y, Cho SY, Kim HS:
Potential role of leptin in angiogenesis: leptin induces endothelial cell
proliferation and expression of matrix metalloproteinases in vivo and
in vitro. Exp Mol Med 2001, 33(2):95–102.
145. Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G,
Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB,
Polverini PJ, et al: Biological action of leptin as an angiogenic factor.
Science 1998, 281(5383):1683–1686.
146. Artwohl M, Roden M, Holzenbein T, Freudenthaler A, Waldhausl W,
Baumgartner-Parzer SM: Modulation by leptin of proliferation and
apoptosis in vascular endothelial cells. Int J Obes Relat Metab Disord 2002,
147. Kume K, Satomura K, Nishisho S, Kitaoka E, Yamanouchi K, Tobiume S,
Nagayama M: Potential role of leptin in endochondral ossification.
J Histochem Cytochem 2002, 50(2):159–169.
148. Diez JJ, Iglesias P: The role of the novel adipocyte-derived hormone
adiponectin in human disease. Eur J Endocrinol 2003, 148(3):293–300.
149. Reis CE, Bressan J, Alfenas RC: Effect of the diet components on
adiponectin levels. Nutr Hosp 2010, 25(6):881–888.
150. Koerner A, Kratzsch J, Kiess W: Adipocytokines: leptin–the classical,
resistin–the controversical, adiponectin–the promising, and more to
come. Best Pract Res Clin Endocrinol Metab 2005, 19(4):525–546.
151. Ishikawa M, Kitayama J, Kazama S, Hiramatsu T, Hatano K, Nagawa H: Plasma
adiponectin and gastric cancer. Clin Cancer Res 2005, 11(2 Pt 1):466–472.
152. Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y,
Noguchi S: Association of serum adiponectin levels with breast cancer
risk. Clin Cancer Res 2003, 9(15):5699–5704.
153. Wang Y, Lam KS, Xu JY, Lu G, Xu LY, Cooper GJ, Xu A: Adiponectin inhibits
cell proliferation by interacting with several growth factors in an
oligomerization-dependent manner. J Biol Chem 2005,
154. Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B,
Funahashi T, Cao Y: Adiponectin-induced antiangiogenesis and antitumor
activity involve caspase-mediated endothelial cell apoptosis. Proc Natl
Acad Sci U S A 2004, 101(8):2476–2481.
155. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T,
Miyagishi M, Hara K, Tsunoda M, et al: Cloning of adiponectin receptors that
mediate antidiabetic metabolic effects. Nature 2003, 423(6941):762–769.
156. Gil-Campos M, Canete RR, Gil A: Adiponectin, the missing link in insulin
resistance and obesity. Clin Nutr 2004, 23(5):963–974.
157. Berkemeyer S: The straight line hypothesis elaborated: case reference
obesity, an argument for acidosis, oxidative stress, and disease
conglomeration? Med Hypotheses 2010, 75(1):59–64.
158. Waris G, Ahsan H: Reactive oxygen species: role in the development of
cancer and various chronic conditions. J Carcinog 2006, 5:14.
159. Malins DC, Haimanot R: Major alterations in the nucleotide structure of
DNA in cancer of the female breast. Cancer Res 1991, 51(19):5430–5432.
160. Malins DC, Polissar NL, Gunselman SJ: Progression of human breast
cancers to the metastatic state is linked to hydroxyl radical-induced
DNA damage. Proc Natl Acad Sci U S A 1996, 93(6):2557–2563.
161. Ichiba M, Maeta Y, Mukoyama T, Saeki T, Yasui S, Kanbe T, Okano J, Tanabe Y,
Hirooka Y, Yamada S, et al: Expression of 8-hydroxy-2'-deoxyguanosine in
chronic liver disease and hepatocellular carcinoma. Liver Int 2003,
162. Schwarz KB, Kew M, Klein A, Abrams RA, Sitzmann J, Jones L, Sharma S,
Britton RS, Di Bisceglie AM, Groopman J: Increased hepatic oxidative DNA
damage in patients with hepatocellular carcinoma. Dig Dis Sci 2001,
163. Feig DI, Reid TM, Loeb LA: Reactive oxygen species in tumorigenesis.
Cancer Res 1994, 54(7 Suppl):1890s–1894s.
164. Retter AS, Gulley JL, Dahut WL: Novel therapeutic strategies in prostate
cancer. Cancer Biol Ther 2004, 3(4):371–376.
165. Sikka SC: Role of oxidative stress response elements and antioxidants in
prostate cancer pathobiology and chemoprevention–a mechanistic
approach. Curr Med Chem 2003, 10(24):2679–2692.
Robey Nutrition & Metabolism 2012, 9:72
Page 10 of 11
166. Vincent HK, Innes KE, Vincent KR: Oxidative stress and potential
interventions to reduce oxidative stress in overweight and obesity.
Diabetes Obes Metab 2007, 9(6):813–839.
167. Mayne ST: Antioxidant nutrients and chronic disease: use of biomarkers
of exposure and oxidative stress status in epidemiologic research. J Nutr
2003, 133(Suppl 3):933S–940S.
168. Green J, Kleeman CR: Role of bone in regulation of systemic acid-base
balance. Kidney Int 1991, 39(1):9–26.
169. Arnett T: Regulation of bone cell function by acid-base balance. Proc Nutr
Soc 2003, 62(2):511–520.
170. Bushinsky DA: Acid-base imbalance and the skeleton. Eur J Nutr 2001,
171. Arnett TR: Acidosis, hypoxia and bone. Arch Biochem Biophys 2010,
172. Arnett TR, Dempster DW: Effect of pH on bone resorption by rat
osteoclasts in vitro. Endocrinology 1986, 119(1):119–124.
173. Arnett TR, Spowage M: Modulation of the resorptive activity of rat
osteoclasts by small changes in extracellular pH near the physiological
range. Bone 1996, 18(3):277–279.
174. Goldhaber P, Rabadjija L: H+stimulation of cell-mediated bone resorption
in tissue culture. Am J Physiol 1987, 253(1 Pt 1):E90–E98.
175. Kraut JA, Mishler DR, Kurokawa K: Effect of colchicine and calcitonin on
calcemic response to metabolic acidosis. Kidney Int 1984, 25(4):608–612.
176. Bushinsky DA, Krieger NS, Geisser DI, Grossman EB, Coe FL: Effects of pH on
bone calcium and proton fluxes in vitro. Am J Physiol 1983,
177. Bushinsky DA: Net calcium efflux from live bone during chronic
metabolic, but not respiratory, acidosis. Am J Physiol 1989,
256(5 Pt 2):F836–F842.
178. Frick KK, Bushinsky DA: Metabolic acidosis stimulates RANKL RNA
expression in bone through a cyclo-oxygenase-dependent mechanism.
J Bone Miner Res 2003, 18(7):1317–1325.
179. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation.
Nature 2003, 423(6937):337–342.
180. Chang L, Karin M: Mammalian MAP kinase signalling cascades.
Nature 2001, 410(6824):37–40.
181. Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H:
Protein expression and functional difference of membrane-bound and
soluble receptor activator of NF-kappaB ligand: modulation of the
expression by osteotropic factors and cytokines. Biochem Biophys Res
Commun 2000, 275(3):768–775.
182. Wada T, Penninger JM: Mitogen-activated protein kinases in apoptosis
regulation. Oncogene 2004, 23(16):2838–2849.
183. Leibbrandt A, Penninger JM: RANK/RANKL: regulators of immune
responses and bone physiology. Ann N Y Acad Sci 2008, 1143:123–150.
184. Gonzalez-Suarez E: RANKL inhibition: a promising novel strategy for
breast cancer treatment. Clin Transl Oncol 2011, 13(4):222–228.
185. Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y, Kumegawa M,
Kimura T, Takeya T: Large scale gene expression analysis of
osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator.
J Biol Chem 2002, 277(43):41147–41156.
186. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M,
Yokochi T, Inoue J, et al: Induction and activation of the transcription factor
NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of
osteoclasts. Dev Cell 2002, 3(6):889–901.
187. Komarova SV, Pereverzev A, Shum JW, Sims SM, Dixon SJ: Convergent
signaling by acidosis and receptor activator of NF-kappaB ligand
(RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts.
Proc Natl Acad Sci U S A 2005, 102(7):2643–2648.
188. Mancini M, Toker A: NFAT proteins: emerging roles in cancer progression.
Nat Rev Cancer 2009, 9(11):810–820.
189. Buchholz M, Schatz A, Wagner M, Michl P, Linhart T, Adler G, Gress TM,
Ellenrieder V: Overexpression of c-myc in pancreatic cancer caused by
ectopic activation of NFATc1 and the Ca2+/calcineurin signaling
pathway. EMBO J 2006, 25(15):3714–3724.
190. Holzmann K, Kohlhammer H, Schwaenen C, Wessendorf S, Kestler HA,
Schwoerer A, Rau B, Radlwimmer B, Dohner H, Lichter P, et al: Genomic
DNA-chip hybridization reveals a higher incidence of genomic
amplifications in pancreatic cancer than conventional comparative
genomic hybridization and leads to the identification of novel candidate
genes. Cancer Res 2004, 64(13):4428–4433.
191. Koenig A, Linhart T, Schlengemann K, Reutlinger K, Wegele J, Adler G, Singh G,
Hofmann L, Kunsch S, Buch T, et al: NFAT-induced histone acetylation relay
switch promotes c-Myc-dependent growth in pancreatic cancer cells.
Gastroenterology 2010, 138(3):1189-1199 e1181-1182.
192. Masuo T, Okamura S, Zhang Y, Mori M: Cyclosporine A inhibits colorectal
cancer proliferation probably by regulating expression levels of c-Myc,
p21(WAF1/CIP1) and proliferating cell nuclear antigen. Cancer Lett 2009,
193. Singh G, Singh SK, Konig A, Reutlinger K, Nye MD, Adhikary T, Eilers M, Gress TM,
Fernandez-Zapico ME, Ellenrieder V: Sequential activation of NFAT and c-Myc
transcription factors mediates the TGF-beta switch from a suppressor to a
promoter of cancer cell proliferation. J Biol Chem 2010, 285(35):27241–27250.
194. Schwalfenberg GK: The alkaline diet: is there evidence that an alkaline pH
diet benefits health? J Environ Public Health 2012, 2012:727630.
Cite this article as: Robey: Examining the relationship between diet-
induced acidosis and cancer. Nutrition & Metabolism 2012 9:72.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
Robey Nutrition & Metabolism 2012, 9:72
Page 11 of 11