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Out of Warburg Effect: an effective cancer treatment targeting the tumor specific metabolism and dysregulated pH



As stated by Otto Warburg nearly a century ago, cancer is a metabolic disease, a fermentation caused by malfunctioning mitochondria, resulting in increased anabolism and decreased catabolism. Treatment should, therefore, aim at restoring the energy yield. To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models. This treatment, in combination with conventional chemotherapy, has yielded extremely encouraging results in glioblastoma, brain metastasis and lung cancer. Randomized trials are necessary to confirm these preliminary data. The major limitation is the fact that the combination of α-lipoic acid and hydroxycitrate can only be effective if the mitochondria are still present and/or functional. That may not be the case in the most aggressive tumors. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Concomitant correction of this alkalosis may be a very effective treatment in case of mitochondrial failure.
Out of Warburg Effect: an effective cancer treatment
targeting the tumor specific metabolism and
dysregulated pH
Laurent Schwartz1*, Thomas Seyfried2, Khalid O. Alfarouk3, 4, Jorgelindo Da Veiga
Moreira5, Stefano Fais6
1Assistance Publique des Hôpitaux de Paris France
2Biology Department, Boston College Chestnut Hill, MA, USA
3Al-Gahd International College for Applied Medical Sciences, Al-Madinah Al-
Munawarah, KSA
4Center for Evolution and Cancer, University of California San Francisco, USA
5 Laboratoire d’informatique Ecole Polytechnique Palaiseau France
6Department of Therapeutic Research and Medicine Evaluation, National Institute of
Health, Rome, Italy
* Corresponding Author:
Laurent Schwartz, MD
Assistance Publique des Hôpitaux de Paris
3 Avenue Victoria, 75004 Paris, France
Tel: +33681899030
E mail:
As stated by Otto Warburg nearly a century ago, cancer is a metabolic
disease, a fermentation caused by malfunctioning mitochondria, resulting in
increased anabolism and decreased catabolism. Treatment should, therefore,
aim at restoring the energy yield. To decrease anabolism, glucose uptake
should be reduced (ketogenic diet). To increase catabolism, the oxidative
phosphorylation should be restored. Treatment with a combination of α-lipoic
acid and hydroxycitrate has been shown to be effective in multiple animal
models. This treatment, in combination with conventional chemotherapy, has
yielded extremely encouraging results in glioblastoma, brain metastasis and
lung cancer. Randomized trials are necessary to confirm these preliminary
data. The major limitation is the fact that the combination of α-lipoic acid and
hydroxycitrate can only be effective if the mitochondria are still present and/or
functional. That may not be the case in the most aggressive tumors. The
increased intracellular alkalosis is a strong mitogenic signal, which bypasses
most inhibitory signals. Concomitant correction of this alkalosis may be a very
effective treatment in case of mitochondrial failure.
Keywords: Warburg’s effect, unification theory, ATP, metabolic treatment,
intracellular alkalosis, ketogenic diet.
In the early 1920’s Otto Warburg demonstrated a unique feature of cancer
cells, namely an increased uptake of glucose and secretion of lactic acid by
cancer cells, even in the presence of oxygen (e.g. the aerobic glycolytic
phenotype) [1,2]. This aerobic fermentation is the signature of cancer [3].
Warburg also noticed a concomitant decreased number of mitochondria
(grana) [4]. In normal, differentiated cells, the yield of a molecule of glucose is
34 ATP. ATP is derived mostly from oxidative phosphorylation which takes
place in the mitochondria [5,6]. In the absence of mitochondria the energy
yield drops to two molecules of ATP per molecule of glucose [5,6]. As stated
by Warburg in the 1920’s, in cancer cells there is a decreased efficacy of the
mitochondria resulting in lesser yield. Despite increased glucose uptake, there
is a 50% drop in ATP level in human colon cancer cells compared to adjacent
benign cells [7]. This decrease in ATP is a consequence of impairment of the
oxidative phosphorylation [6–9].
To compensate for the decreased energy yield, the cell increases its glucose
uptake [7,10]. The decreased activity of the mitochondria has many
consequences, one of which is an increased secretion of lactic acid and
another one is the activation of the pentose phosphate pathway (PPP).
Another consequence is the activation of the glutaminolysis which is
necessary for nucleic acid synthesis [6–9].
The activation of the Pentose Phosphate Pathway results from an increase in
glucose uptake with a concomitant obstacle downstream of the pentose
phosphate shunt, most probably at the level of pyruvate dehydrogenase
and/or of pyruvate kinase [2,6,11]. The increased flux in the pentose
phosphate pathway results in:
A shift toward anabolism due to increased synthesis of NADPH that
plays a crucial role in NDPH/NADP+ ratio that determines the redox
state of the cell via removal of reactive oxygen species (ROS) and so
prevents cellular death and controls cellular fate [7,11].
The shift toward the pentose pathway also results in the production of
ribose-5-phosphate, required for the synthesis of nucleic acids [5].
One other crucial consequences of the mitochondrial defect is intracellular
alkalosis [7]. Tumors show a 'reversed' pH gradient with a constitutively
increased intracellular pH that is higher than the extracellular pH. This
gradient enables cancer progression by promoting proliferation, the evasion of
apoptosis, metabolic adaptation, migration, and invasion [12–15].
There is evidence that an acidic extracellular pH promotes invasiveness and
metastatic behavior in several tumor models [14,16], proteolytic enzyme
activation and matrix destruction [17–19].
In normal cells, the intracellular pH (pHi) oscillates during the cell cycle
between 6.8 and 7.3 [7]. The oscillation of the pH during the cell cycle
matches the value of the decompaction of the histones, RNA polymerase
activation, DNA polymerase activation and DNA compaction before mitosis
The intracellular pH of the cancer cells has been less studied. During the cell
cycle, it oscillates between 7.2 and 7.5. Intracellular alkalosis is probably a
consequence of the decreased oxidative phosphorylation resulting in
decreased secretion of carbon dioxide (CO2) and the CO2 reacts with water to
create carbonic acid. Cell transformation or enhanced cancer cell division and
resistance to chemotherapy are all associated with a more alkaline pHi [20–
The very reason of the dysfunction of the mitochondria is still open for debate.
No tumor cell has yet been found with a normal content or composition of
cardiolipin, the signature lipid of the inner mitochondrial membrane. This lipid
regulates the efficiency of OxPhos [9,10].
The Warburg effect may be a direct consequence of the activation of
oncogenes [6]. Infection by an oncogenic virus or exposure to a carcinogen
inhibits the mitochondrial function and causes the Warburg’s effect [24–28].
As Warburg wrote in 1956 [4,29], “The chicken Rous sarcoma virus, which is
labeled today as a virus tumor, ferments glucose, and lives as a partial
anaerobe like all tumors.” Infection by an oncogenic virus or exposure to a
carcinogen inhibits the mitochondrial function and causes the Warburg’s effect
Alternatively, the Warburg effect results in oncogene activation and mutation.
Oncogene up-regulation is needed to drive fermentation after OxPhos
dysfunction. Mitochondria replacement will activate OxPhos and turn off
oncogenes [9,10].
This Warburg’s effect is responsible for the activation of the Pentose
phosphate pathway, glutaminolysis and subsequent anabolism [9] and all
thirty different oncogenes target and stimulate the anabolic pathways [9].
The introduction of normal mitochondria into cancer cells restores
mitochondrial function, inhibits cancer cell growth and reverses
chemoresistance [30,31]. Also the fusion of cancer cells with normal
mitochondria results in increased ATP synthesis, oxygen consumption and
respiratory chain activities together with marked decreases in cancer growth,
resistance to anti-cancer drugs, invasion, colony formation in soft agar, and «
in vivo » tumor growth in nude mice [31].
Reversing the Warburg effect:
Cytotoxic chemotherapy has had tremendous benefits for pediatric or
Hodgkin’s patients. However, for most solid tumors, while there is a sizable
response rate (complete and partial regression), there has been a limited gain
in survival.
The mechanism of action of cytotoxic chemotherapy is debated. Response to
cytotoxic drugs is assessed by PET scan. Effective treatment results in
decreased radiolabelled glucose. Most cytotoxic drugs target (indirectly) the
mitochondria and the Warburg effect [32–35]
As the Warburg aerobic glycolytic phenotype and its effects on metabolism
are key to cancer, the obvious question is whether drugs can be designed to
target it. To alleviate the Warburg effect, pyruvate should be converted into
Acetyl-CoA, which would decrease the bottleneck that results in the activation
of both the Pentose Phosphate Pathway and the glutaminolysis. The
mitochondrial yield should be increased to stimulate the synthesis of CO2 and
the increased secretion of CO2 would result in a decreased intracellular
The combination of α-lipoïc acid and hydroxicitrate [36–39] has been reported
to slow cancer growth, in murine xenografts. This inhibition appears to be
independent of the primary tumor site and has been reproduced in different
laboratories [40,41].
The most likely mechanism of action for α-lipoic acid in its reduction of tumor
growth is the inhibition of pyruvate dehydrogenase kinase (the same target of
Dichloroacetic acid (DCA)). This enzyme inhibits the activity of pyruvate
dehydrogenase and is known to be up-regulated in cancer cells expressing
the Warburg aerobic glycolytic phenotype. Pyruvate dehydrogenase catalyses
the conversion of pyruvate to acetyl-CoA, the initial step of the final
conversion of glucose to carbon dioxide and water in the TCA cycle, with the
concomitant production of ATP. Therefore, it is reasonable to suggest that
blocking the activity of pyruvate dehydrogenase kinase will at least partially
restore the activity of pyruvate dehydrogenase, thereby increasing the flux of
pyruvate through the TCA cycle in the mitochondria, while simultaneously
reducing the production of lactic acid and most importantly decreasing the flux
in the pentose pathway shunt [9].
There are several reports of metabolic treatment utilizing a combination of α-
lipoic acid and hydroxycitrate together with conventional cancer therapy.
Starting in January 2013, metabolic treatment (α-lipoic acid/hydroxycitrate
with low doses of the chemotherapic plus Naltrexone) was offered to patients
sent home after the failure of conventional cytotoxic chemotherapy for
metastatic cancer (irrespective of the primary site) but with a Karnovsky
performance status above 70 (quantification cancer patients' general well-
being and activities of daily life) [42–46]. Of the first randomly selected eleven
patients, five were alive and reasonably well 30 months after the start of
treatment [43]. From our experience, the combination of α-lipoic
acid/hydroxycitrate with low dose Naltrexone was able to prevent tumor
recurrence in only two patients. The patients who survived for more than one
year were treated with a combination of standard care with metabolic
In the update of a subsequent study, patients with multiple brain metastasis
(n=4) or glioblastoma (n=6) were treated with a combination of conventional
and metabolic treatments (α-lipoic acid/hydroxycitrate) as well as ketogenic
diet. Five out of six patients with glioblastoma were alive and stable after two
years, while two of the four patients with multiple brain metastases are alive
and well three years later [46]. These glioblastoma patients had concomitant
radiation therapy and chemotherapy (temozolamide).
In another study, four lung patients (primary adenocarcinoma) were treated
with a combination of the small molecule EGFR inhibitor, Gefitinib, and
metabolic treatment (α-lipoic acid/hydroxycitrate). They all responded to
treatment and are stable one year after the start of therapy. These very
encouraging results need to be confirmed by further randomized clinical trials.
Correcting the intracellular alkalosis :
Correcting the intracellular pH may be an alternative or an adjunct to a
metabolic treatment as there is extensive literature that many effective cancer
treatments decrease the intracellular pH (pHi) [2,23,47]: literature on
increased survival support for the combined use of antacids (which prevent
proton extrusion from the tumour cells) with standard chemotherapy [15,48–
51]. Hyperthermia [50] decreases the intracellular pH.
There are two possibilities to decrease the intracellular pH (pHi). The first is a
calorie restricted ketogenic diet [8], which will reduce the availability of
glucose, the principal metabolite for glycolysis and the PPP. This diet will
result in increased levels of acidic ketone bodies that cannot be metabolized
by the cancer cells (while normal cells are able to do so) and this probably
results in a decrease of the intracellular pH. Similarly, it has been proposed
that an acid diet in general might lead to a supply of lactate (exogenous
lactate) that might lead to regression of the tumour growth [51].
The rapid turnover of aberrantly dividing cancer cells within the tumor mass,
sugar fermentation and increased ATP hydrolysis, all lead to the production
and release of large amounts of protons into the extracellular compartment
[1,52]. The H+ accumulation, in turn, leads to the progressive setting of a
highly hostile microenvironment, mostly characterized by low pH. The acidic
microenvironment produces a sort of “selective pressure,” that, in fact, favors
the cells that are best adapted to survive in these hostile conditions. The
hostility of the microenvironment is increased by hypoxia and low nutrient
supply, making it virtually impossible for “normal” or more differentiated cells
to survive in these unsuitable conditions. To thrive in such an unfavorable
microenvironment, tumor cells must develop systems to actively extrude
excess protons [48,52–55]. These mechanisms include the V-ATPase, the
Na+/H+ exchanger (NHE), monocarboxylate transporters (MCTs) and carbonic
anhydrase 9 [52]. Of course, we must consider these proton exchangers as
key “survival options” for cancer cells, and, therefore, depriving cancer cells of
their function should inevitably lead to a rapid cell death due to internal
acidification, as it has been shown for different cancer cell types in pre-clinical
settings [56,57]. Unfortunately, it is very hard to convince clinical oncologists
to use this approach in a first line treatment of cancer patients. However, it
was possible to increase the proof of principle that at least proton pump
inhibitors may be included in new anti-cancer protocols together with the
standard treatments. Clinical evidence has been provided in human tumor
patients with either osteosarcoma [58], breast cancer [59] or GI cancers [60].
Further evidence has been accumulated in clinical trials have been performed
in domestic animals with spontaneous tumors of different histotypes, with very
encouraging results [61,62]. Altogether, these pre-clinical and clinical results
suggest that a way to counteract intracellular alkalinity might be to inhibit the
above mechanisms designed to avoid intracellular acidification.
Today, cancer is thought to be a set of very complex diseases with thousands
of different mutations. That apparent complexity has led to personalized
medicine. However, modern biology has confirmed the universality of the
Warburg aerobic glycolytic phenotype. Furthermore, the fact that the
combination of α-lipoïc acid and hydroxycitrate slows down cancer growth in
every tumor model studied to date suggests that at least some targets are the
same in a large spectrum of tumors.
The Warburg effect can be caused by two intertwined phenomena. The first is
a metabolic bottleneck, which can be corrected. The second is the
destruction/disappearance of the mitochondria.
Cytotoxic drugs injure or even destroy the mitochondria [32–35]. At the time of
failure of chemotherapy, there is a sharply increased glucose uptake such as
seen on PET scan [63]. Resistance to chemotherapy has been correlated with
mitochondrial functionality (perhaps oxidative phosphorylation) [64] and
alkaline pHi [1,23]. The oxidative phosphorylation is further reduced; the pH is
more alkaline, and the PPP is activated. Cancer grows relentlessly, and
further chemotherapy is usually ineffective [9].
Further studies should assess the role of low dose chemotherapy together
with a combination of metabolic treatment and treatments to lower the
intracellular pH.
Conflict of Interest statement:
The authors declare that they have no competing interests.
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... The increase of internal pH is parallel to a decrease of external pH, due to the release of lactic acid by cancer cells [30]. Lactic acid is a nutrient for the surrounding immune cells and for the vascular cells [31,32]. This acidification of the extracellular environment favors the cells that are best adapted to these hostile conditions. ...
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Cancer cells are very diverse but mostly share a common metabolic property : they are strongly glycolytic even though oxygen is available. Herein, the metabolic abnormalities of cancer cells are interpreted as modifications of the electric currents in redox reactions. A lower current in the electron transport chain, an increase of the concentration of reduced cofactors and a partial reversal of the tricarboxylic acid cycle are physical characteristics of several forms of cancer. The existence of electric short-circuits between oxidative branches and reductive branches of the metabolic network argue in favor of an electronic approach of cancer in the nanoscopic scale. These changes of electron flows induce a pseudo-hypoxia and the Warburg effect through succinate production and divert electrons from oxygen to biosynthetic pathways. This new look at cancer may have potential therapeutic applications. Abstract : Cancer cells are very diverse but mostly share a common metabolic property: they are strongly glycolytic even though oxygen is available. Herein, the metabolic abnormalities of cancer cells are interpreted as modifications of the electric currents in redox reactions. A lower current in the electron transport chain, an increase of the concentration of reduced cofactors and a partial reversal of the tricarboxylic acid cycle are physical characteristics of several forms of cancer. The existence of electric short-circuits between oxidative branches and reductive branches of the metabolic network argue in favor of an electronic approach of cancer in the nanoscopic scale. These changes of electron flows induce a pseudo-hypoxia and the Warburg effect through succinate production and divert electrons from oxygen to biosynthetic pathways. This new look at cancer may have potential therapeutic applications.
... Upregulation in glucose influx was associated with tumor growth and onco-metabolism. The increase in glucose influx has been associated with vasculogenesis and angiogenesis (68). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A c c e p t e d M a n u s c r i p t 36 Glutaminolysis-induced lactate secretion was strongly associated with angiogenesis, tumor migration, and growth (80). The highest elevated serum LDH level was observed in the lambdainduced group compared to normal control and other induced groups (69). ...
Glioblastoma has been recognized as a most perilous and highly malignant type of primary brain tumor. The rapid progression brain tumor model was developed by direct intracranial administration of ENU at the different focal brain points in the rat brains. The GQD was synthesized by bottom-up technique and functionalized with Trastuzumab and Caspase-8 antibody by Carbodiimide-amidation activation. The in-vitro cytotoxicity MTT assay was performed with all the GQD conjugates in SK-N-SH and N2a cell lines. The acute and chronic toxicity of synthesized GQD was performed in healthy rats and evaluated the hemolytic activity and CRP levels. A synthesized quasi-spherical 2-D tiny GQD has a particle size of less than 10 nm and a 12.7% quantum yield. The GQD conjugates were characterized by DSL, TEM, AFM, FTIR, and Fluorescence spectroscopy. In-silico molecular docking was a conformed static interaction between GQD and antibodies. GQD-conjugates showed dose-dependent toxicity in both cell lines and mild acute toxicity in rat blood. The GBM tumor-bearing rats were assessed for the anti-cancer and neuroprotective activity of the GQD conjugates. Histopathology, immunohistochemistry, metabolic, and inflammatory tumor biomarker estimation showed that the GQD_Caspase-8 conjugate showed better anti-tumor and neuroprotective effects as compared to other conjugates.
... Until now, energy produced by glycolysis has been widely regarded as a main energy source for tumor cells. 27 In this study, we found that the combination treatment significantly reduced glycolytic function but not mitochondrial respiration in AML cells, suggesting that the VEN+SEL combination promoted apoptosis of AML cells by inhibiting anaerobic glycolysis rather than oxidative phosphorylation (OXPHOS). Therefore, it was speculated that the VEN+SEL combination might exert its apoptotic biological functions in AML by inhibiting glycolysis. ...
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Introduction The BCL-2 inhibitor venetoclax has been widely used in the treatment of acute myeloid leukemia (AML); however, AML patients treated with venetoclax gradually develop resistance. The exportin-1 (XPO1) inhibitor selinexor can synergistically promote the antileukemia activity of venetoclax, but the mechanism remains unclear. Methods and Results Annexin V/7-aminoactinomycin D assays were used to examine the effects of a combination of venetoclax and selinexor (VEN+SEL) on AML cell lines and primary AML cells. RNA sequencing and oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) determinations by a Seahorse XF analyzer were employed to investigate the molecular mechanism of the toxicity of the VEN+SEL combination to AML cells. The cytotoxicity of NK cell combined with VEN+SEL combination was assessed in vitro using flow cytometry. VEN+SEL enhanced the apoptosis of AML cells (KG-1A and THP-1) and primary AML samples in vitro. The ECAR and OCR results demonstrated that the VEN+SEL combination significantly inhibited glycolytic function. RNA sequencing of THP-1 cells demonstrated that DNA replication-related genes were downregulated after treatment with the VEN+SEL combination. Conclusion This study indicated that selinexor can synergistically enhance the antileukemia activity of venetoclax in AML cells in vitro by inhibiting glycolytic function and downregulating DNA replication-related genes. Based on our experimental data, combining selinexor with venetoclax is an appropriate advanced treatment option for AML patients.
... Moreover, in this line, our group has proposed new pH-dependent avenues for the treatment of human malignancies, ranging from brain tumors [29] to breast cancer [51,52] to other malignancies [28,30]. During the last few years, other groups have also activated clinical efforts to exploit the significantly diseased pH-related metabolic aspects of malignant tumors in cancer treatment [70,71]. ...
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A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “theWarburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addresses the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications. At one point, Warburg also said: "The causes pf cancer are countless, but they all work through the same mechanism". And this mechanism was not aeroblic glycolysis, as Warburg defended all his life, but the main cause behind aerobic glycolysis, namely, intracellular alkalinization. Keywords: pH in cancer primal etiology; Warburg effect nowadays; changing hallmarks in cancer; historical mishaps in metabolic cancer research; integrations among orthodox and heterodox oncology; pH-related therapeutic implications
Background and Objectives 4-Methylumbelliferone (4-MU) is a coumarin compound that can be extracted from the medicinal plant with anti-cancer properties, Smilax china L. In recent years, studies have revealed its potential as an anti-tumor and anti-metastasis drug with promising effects in cancer treatment. Despite an increase in research on the metabolic patterns of tumor cells, no prior research has suggested that 4-MU inhibits tumor proliferation by blocking glycolysis. This thesis presents evidence that 4-MU binds to proteins involved in glycolysis, thus mediating its anti-tumor effects. Materials and Methods Network pharmacology, transcriptomics, and molecular docking were utilized to forecast the potential targets and probable pathways of 4-MU’s anti-cancer activity, and the affinity of 4-MU towards potential targets was discovered using microscale thermophoresis (MST) detection. Results The results of transcriptome analysis brought to light that the genes with differential expressions were primarily enriched in metabolic pathways, including glycolysis-related proteins. Using network pharmacology and molecular docking, our study identified Heat Shock Protein 90 Alpha Family Class A Member 1 (Hsp90AA1), mitochondria, phosphoglycerate kinase 2 (PGK2), glycerol-3-phosphate dehydrogenase (GPD2), and glucose-6-phosphate isomerase (GPI) as potential targets of 4-MU. The strong binding affinity between 4-MU and these proteins was confirmed by the MST assay. Conclusion The findings indicate that 4-MU can hinder glycolysis by binding to glycolysis-associated proteins such as Hsp90AA1, PGK2, GPD2, and GPI. This results in the prevention of the energy supply to the tumor tissue, which ultimately curbs tumor growth, thereby demonstrating its anti-tumor properties. These results conclude that 4-MU has the capacity to be a novel glycolysis inhibitor for cancer treatment. Moreover, the identification of these glycolysis-associated proteins as possible targets for cancer therapy offers new avenues for research in the field of cancer treatment, thus providing further valuable evidence for the anti-cancer mechanism of 4-MU.
Intrinsically disordered proteins and protein regions (IDRs) are abundant in eukaryotic proteomes and play a wide variety of essential roles. Instead of folding into a stable structure, IDRs exist in an ensemble of interconverting conformations whose structure is biased by sequence-dependent interactions. The absence of a stable 3D structure, combined with high solvent accessibility, means that IDR conformational biases are inherently sensitive to changes in their environment. Here, we argue that IDRs are ideally poised to act as sensors and actuators of cellular physicochemistry. We review the physical principles that underlie IDR sensitivity, the molecular mechanisms that translate this sensitivity to function, and recent studies where environmental sensing by IDRs may play a key role in their downstream function.
Nanomaterial-based cancer therapy faces significant limitations due to the complex nature of the tumor microenvironment (TME). Starvation therapy is an emerging therapeutic approach that targets tumor cell metabolism using glucose oxidase (GOx). Importantly, it can provide a material or environmental foundation for other diverse therapeutic methods by manipulating the properties of the TME, such as acidity, hydrogen peroxide (H2O2) levels, and hypoxia degree. In recent years, this cascade strategy has been extensively applied in nanoplatforms for ongoing synergetic therapy and still holds undeniable potential. However, only a few review articles comprehensively elucidate the rational designs of nanoplatforms for synergetic therapeutic regimens revolving around the conception of the cascade strategy. Therefore, this review focuses on innovative cascade strategies for GOx-based synergetic therapy from representative paradigms to state-of-the-art reports to provide an instructive, comprehensive, and insightful reference for readers. Thereafter, we discuss the remaining challenges and offer a critical perspective on the further advancement of GOx-facilitated cancer treatment toward clinical translation.
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It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. The goal of this paper is to suggest strongly that most (if not all) the hallmarks of cancer could be the consequence of the Warburg‘s effect. As a result of the metabolic impairment of the oxidative phosphorylation, there is a decrease in ATP concentration. To compensate the reduced energy yield, there is massive glucose uptake, anaerobic glycolysis, with an up-regulation of the Pentose Phosphate Pathway resulting in increased biosynthesis leading to increased cell division and local pressure. This increased pressure is responsible for the fractal shape of the tumor, the secretion of collagen by the fibroblasts and plays a critical role in metastatic spread. The massive extrusion of lactic acid contributes to the extracellular acidity and the activation of the immune system. The decreased oxidative phosphorylation leads to impairment in CO2 levels inside and outside the cell, with increased intracellular alkalosis and contribution of carbonic acid to extracellular acidosis-mediated by at least two cancer-associated carbonic anhydrase isoforms. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Mitochondrial disappearance (such as seen in very aggressive tumors) is a consequence of mitochondrial swelling, itself a result of decreased ATP concentration. The transmembrane pumps, which extrude, from the mitochondria, ions, and water, are ATP-dependant. Therapy aiming at increasing both the number and the efficacy of mitochondria could be very useful.
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Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumour microenvironment acidification thus restoring chemotherapeutic sensitivity. Moreover, several clinical data supports the role of cytotoxic drugs at low-dose continuously delivered as anticancer therapy. Methods: Clinical records of three patients affected with gastrointestinal cancer refractory to standard treatments, who had received a combination of high-dose rabeprazole and metronomic chemotherapy were reviewed. Results: The first case, a 78-year-old man was treated for lung metastasis from colon adenocarcinoma. The second case, a 73-year-old man was treated for metastatic rectal cancer to the liver. The third one, a 68-year-old man, underwent the combination regimen for colon cancer with lung, liver and peritoneal metastases. Conclusions: Despite the failure of previous standard chemotherapy for metastatic disease, good clinical outcome was shown in these patients treated with an unconventional association of high-dose PPIs and metronomic chemotherapy.
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Background: The combination of hydroxycitrate and lipoic acid has been demonstrated by several series of experiments in several laboratories to be effective in reducing murine cancer growth. Patients and Methods: Forty patients with advanced incurable cancers were treated by metabolic treatment. All had been given a dismal prognosis with a life expectancy ranging between two and six months. All the patients were given a metabolic treatment, independently of the nature of the primary cancer. A first group of patients were treated by this metabolic treatment alone. A second group of 27 received simultaneously a conventional cytotoxic chemotherapy. A third group of 4 patients were simultaneously treated by hormonotherapy. Results: Side effects of metabolic treatment are mild. The one year survival of the first group of patients was 68%. The one year survival of the group of patients treated with chemotherapy and metabolic treatment was 70%. The two hormone resistant prostate cancers experienced a drastic decrease in PSA. These results are in line with published animal data. Randomized clinical trials are being defined to confirm the major efficacy of metabolic treatment.
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Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC). Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m 2 followed by cisplatin 75 mg/m 2 on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate. Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 % vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI. The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial. Trial registration identifier: NCT01069081.
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Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor‑related factors. However, most current research is focused on tumor‑specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer.
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The different phases of the eukaryotic cell cycle are exceptionally well-preserved phenomena. DNA decompaction, RNA and protein synthesis (in late G1 phase) followed by DNA replication (in S phase) and lipid synthesis (in G2 phase) occur after resting cells (in G0) are committed to proliferate. The G1 phase of the cell cycle is characterized by an increase in the glycolytic metabolism, sustained by high NAD(+)/NADH ratio. A transient cytosolic acidification occurs, probably due to lactic acid synthesis or ATP hydrolysis, followed by cytosolic alkalinization. A hyperpolarized transmembrane potential is also observed, as result of sodium/potassium pump (NaK-ATPase) activity. During progression of the cell cycle, the Pentose Phosphate Pathway (PPP) is activated by increased NADP(+)/NADPH ratio, converting glucose 6-phosphate to nucleotide precursors. Then, nucleic acid synthesis and DNA replication occur in S phase. Along with S phase, unpublished results show a cytosolic acidification, probably the result of glutaminolysis occurring during this phase. In G2 phase there is a decrease in NADPH concentration (used for membrane lipid synthesis) and a cytoplasmic alkalinization occurs. Mitochondria hyperfusion matches the cytosolic acidification at late G1/S transition and then triggers ATP synthesis by oxidative phosphorylation. We hypothesize here that the cytosolic pH may coordinate mitochondrial activity and thus the different redox cycles, which in turn control the cell metabolism.
Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide substantial new evidence that altering the acidic tumor microenvironment is an effective, well tolerated and low cost strategy for the overcoming of anticancer drug resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.