You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


pH in Cancer & Tumor Acidification: A Top Treatment Strategy

Summary:

pH and Cancer is an intensively discussed subject both in the alternative treatment arena and fortunately more and more in the scientific arena. In terms of treatments, when we speak about pH in cancer I am thinking of treatments involving e.g. the well known Sodium Bicarbonate, Cesium Chloride, Germanium, etc. I am also thinking of diets such as the alkaline diet. However, although all of these have their own relevance, these are not the approaches that I intend to discuss in this article. Instead, I will discuss a treatment approach that for some may be new but one that has been already used by some of the most open minded oncologist of this world to treat cancer patients while achieving great results. Here is a nice example of that: Ref.

According to the reference above, the Spanish Dr. Salvador Harguindey is maybe the first and one of the few clinical oncologist worldwide who experimented this approach in cancer patients. He is also one of the leaders of the Association for Proton Cancer Research and Treatment, a fast growing association of scientists working on solving the cancer challenge via a pH perspective.

I strongly believe that manipulating pH is a major way to fight cancer.

Note that manipulating pH is not only relevant as a stand alone anti cancer strategy but it can also be a way to reduce or eliminate some of the main resistance mechanism of tumors to chemotheraphy (Ref.1Ref2, Ref3, Ref4, Ref5, Ref6).

Update 02-April-2017: Please note that pH manipulation may affect the effectiveness of chemo both ways depending on the type of chemo and the chosen pH strategy. This is further discussed in the “Mechanism” section.

Mechanisms:

Before going into the discussion of the concept of this relatively new treatment strategy, I would like to clarify a bit the framework. I will not go to deep into the scientific details, but just enough so that we understand the concept.

First, it is important to realize that when speaking about pH many think that the pH in cancer is low. That is true but only partially. That is because indeed the pH is low around the tumors but not inside the tumor cells. Instead, the intra cellular pH in the cancer cells is usually higher compared to the normal cells. This is a bit “strange” given that cancer cells are producing a lot of acidity (i.e. protons) while generating their energy.

Indeed, it is well known that cancer cells are using a lot of glucose to produce energy and other elements required for their existence. Due to the fact that the engine of the cell (mitochondria) works slower than usually or doesn’t work at all in some cases, cancer cells uses another mechanism to produce energy and the other components. This alternative mechanism is called glycolisis or better known as fermentation. However, fermentation is a less effective mechanism compared to the usual cell respiration and as a result it requires more glucose to produce the same amount of energy. This intensive use of glucose leads not only to energy production but as a side effect, it produces a lot of protons (i.e. acidity).

Since the cancer cells like to have high pH (i.e. low acidity) inside (i.e. in the cytosol), they developed a way to push all that outside the cell. In order to push the acidity out, the cancer cells developed much more acidity transporters compared to the normal cells. Some of the most relevant and well known transporters are:

Sodium/Hydrogen exchange, an antiporter which enables the cells to exchange protons for Sodium, i.e. Sodium in and acidity out – maybe the most relevant for balancing the pH – well known to be over expressed in many cancers. We may even argue here that as a cancer patient eating a lot of salt will add enough sodium in our body to keep this pump running well, which is not something we want.

Carbonic anhydrase 9 (CAIX) this is an enzyme that helps extracellular CO2 to become HCO3 (bicarbonate ion). This bicarbonate ion than goes into the cell via the bicarbonate transporter and combines (via CAII enzyme) with a proton resulting CO2 and H20 which are finally pushed out through the cell membrane. This is a way for the cancer cell to annihilate intracellular protons and thus mantain an increased intracellular pH – well known to be over expressed in many cancers (Ref.1, Ref.2, Ref.3)

Monocarboxylate 4 (MCT4) – a transporter that exports lactate, another result of glycolisis, and proton as lactic acid into the tumor environment – well known to be over expressed in many cancers (Ref.)

acidification of the tumor can also be achieved by reduction in blood flow to tumors relative to normal tissues (Ref.)

Interestingly, drugs that modulate the above “knobs” are all known to have strong anticancer effects via various mechanisms other than pH modulation. However, only recently it has been identified that what they all have in common is their influence on pH.

Therefore, using mechanism such as those mentioned above, cancer cells are pushing the acidity from inside out so that a balanced internal pH is maintained. As a result, tumors have a lower extracellular pH (6.7–7.1) than normal tissues (7.4). (Ref.) Beside the fact that the intracellular pH stays as required for the normal function of cancer cells, this acidity export additionally helps the tumors with the following:

lactic acid serves as fuel for other cancer cells that have the capability to import lactate and use it to produce energy via normal respiration

acidity promotes the metastasis process

acidity inhibits the immune system by inhibiting the MCT1 in T cells (Ref1, Ref2)

acidity reduces or cancels the effect of chemotheraphies that are week basis

and much more ….

pH and Chemo

Update 02-April-2017: pH manipulation may affect the effectiveness of chemo both ways depending on the type of chemo and the chosen pH strategy:

If the chemo used is a weak basis (such as Gemcitabine, Doxorubicin, Daunorubicin, Mitoxantrone, Epirubicin, Idarubicin, Valrubicin, Bleomycin, Vinca alkaloids, etc.) (Ref.1, Ref.2) low pH around the tumors may reduce or inhibit the effect of chemotherapy as the chemo will be “deactivated” before accessing the tumor (Ref.). Therefore, when using such chemos, using strategies to increase the pH (i.e. lower acidity) prior to chemo can increase the effectiveness of chemos (Ref.1, Ref.2, Ref.3)
Epirubicin, for example also a weak base with a pKa of 8.1 and has been shown to exhibits increased efficacy against cancer in alkaline environment. (Ref.)

Note that the weak basis chemotheraphies such as Doxorubicin have been shown to undergo ion trapping and sequestration into acidic vesicles within the cytoplasm. This process has been associated with drug resistance (Ref. and here is available as a pdf). In simple words, if the weak base type of chemo succeeds to pass through the acidic environment and enter the cancer cells, chemo may be attracted like a magnet in to some storage rooms within the cells and made inactive (Ref.).These storage rooms (lysosomes) attract chemo because they are acidic. In order to lower their acidity and stop them trapping chemo, we can consider the use of drugs known to lower lysosome acidity. One such drug is Omeprazole (Ref.).

On the other hand, if the chemo is weak acid (such as Cyclophosphamide, 5-Flourouracil*, Chlorambucil, Cisplatin**, Carboplatin, Mitomycin C, Melphalan, etc.) (Ref.1, Ref.2), low extracellular pH (i.e. higher acidity) will leads to enhanced absorption and cytotoxicity (Ref.1, Ref.2, Ref.3). Same seems to apply for Capecitabine (Xeloda) (Ref.). Therefore for these or similar chemos, proton pump inhibitors are best avoided.

**Cisplatin is a weak acid (Ref.1), however it seems that in some cases it is also potentiated by a strategy focused on increasing extracellular pH (Ref.). Yet, it is not very clear to me if the Platins are on the acid or base side according to the following reference (Ref.) but also various papers some claiming it is base (Ref.) and others acid (Ref.).
This article suggests Cisplatin is an acid: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502609/

cancer cells like to have an internal pH relatively high, higher than that inside normal cells

cancer cells are intensively producing acidity during the energy production process, and this needs to be pushed out

Based on these specific characteristics of cancer cells we can imagine the following treatment strategies that can work against cancer cells:

Intracellular Alkalinization: increase further the intracellular pH of cancer cells (using e.g. Cesium Chloride, Germanium) to a level that is not sustainable for the cancer cells

Intracellular Acidification: decrease the intracellular pH of cancer cells to a level that is not sustainable for the cancer cells (additionally this will lead to a increase of extracellular pH)

Extracellular Alkalinization: increase of the extracellular pH (e.g. using sodium bicarbonate, alkaline diet, etc.) to create an environment unsuitable for cancer growth and activate the immune system. (Ref.) Note, that in contrast to many statements from various people arguing that oral Bicarbonate can not induce a change of tumor extracellular pH since the blood pH is constantly adjusted and maintained to a stable value by various mechanisms in the human body, it has been shown that actually that oral Bicarbonate can indeed change the pH at the tumor site and can even reverse the pH gradient (Ref.)

One of the most powerful technique in my opinion is to focus on further decreasing the intracellular pH, i.e. internal acidification. The concept is very simple and it may be easier to achieve compared to the strategy to further increasing the internal pH (alkalinization), since the cancer cells are continuously producing acidity. Intracellular acidification can be achieved by inhibiting some or all of the major acidity transporters discussed above. Actually this strategy can be seen as pushing a banana or a potato into the exhaust pipe of a car so that the smoke can not go out. Since some cancers may use multiple “exhaust pipes” all these pipes may need to be inhibited for the best effect while in others such as melanoma one “pipe” only inhibition (MCTs inhibition only) may be enough (Ref.). On the same line, in a case of ovarian cancer, Sodium/Hydrogen inhibition was enough (Ref.)

This strategy not only puts pressure on the cancer cells due to the intracellular acidification but also leads to immune activation (Ref.), increase chemo effectiveness and reduced chance of metastasis.

Intracellular acidification and its application:

Here are some elements that can be used alone or in combination with a focus on reducing or inhibiting the major acidity exporters and the related doses as indicated in various publications:

Acidification of the tumor can also be achieved by reduction in blood flow to tumors relative to normal tissues (Ref.) The vasodilator hydralazine is thought to act on the arteriolar smooth muscle, and since a large proportion of tumor blood vessels lack smooth muscle, they do not respond to the drug. As a result it has been argued that this leads to a redistribution of cardiac output away from the tumor, thus selectively reducing tumor blood flow, with a consequent reduction in tumor pH. Indeed it was shown a 0.4 pH unit drop in tumor pHi 20–40 min following intravenous administration of hydralazine to RIF-1 tumor-bearing mice (Ref.1, Ref.2) Note, I would not use hydralazine in combination with chemo as it would lead to lower blood flow to the tumor and thus less drug available at the tumor site.

Safety:

Note that Amiloride usage may lead to increase of potassium in the blood which can be dangerous. So I would make sure a doctor is following the patient with blood tests every two weeks.

Watching calcium levels is prudent when taking a PPIs such as Omeprazole.

Source:

Amiloride, Acetazolamide, Statins (drugs on prescription) are available at online pharmacies such as http://www.buy-pharma.co/

Omeprazole is over the counter drug or can also be probably found at the pharmacies above and on eBay.

BACKGROUND: 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).
METHODS: 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.
RESULTS: 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 (67.7 % vs. 46.9 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045) [corrected]. 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.
CONCLUSIONS: 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.

Cimetidine: “It is generally preferred to pre-treat the tumour patient with another antacid, such as calcium carbonate, or antacid drug, such as an H2-receptor antagonist, for example ranitidine or cimetidine, in order to inhibit acid secretion in the stomach, thereby enhancing the concentration of PPI able to reach the tumour site, and minimising the concentration remaining in the stomach. Thus, treatment with an antacid is effective to increase the delivery of PPI to the acidic tumour, as the number of only acidic sites in the body is substantially reduced or, at least, the most significant site is temporarily neutralised, or ameliorated.” http://www.google.com/patents/EP1713481B1?cl=en

In recent years an increasing number of publications have emphasized the growing importance of hydrogen ion dynamics in modern cancer research, from etiopathogenesis and treatment. A proton [H+]-related mechanism underlying the initiation and progression of the neoplastic process has been recently described by different research groups as a new paradigm in which all cancer cells and tissues, regardless of their origin and genetic background, have a pivotal energetic and homeostatic disturbance of their metabolism that is completely different from all normal tissues: an aberrant regulation of hydrogen ion dynamics leading to a reversal of the pH gradient in cancer cells and tissues (↑pHi/↓pHe, or “proton reversal”). Tumor cells survive their hostile microenvironment due to membrane-bound proton pumps and transporters, and their main defensive strategy is to never allow internal acidification because that could lead to their death through apoptosis. In this context, one of the primary and best studied regulators of both pHi and pHe in tumors is the Na+/H+ exchanger isoform 1 (NHE1). An elevated NHE1 activity can be correlated with both an increase in cell pH and a decrease in the extracellular pH of tumors, and such proton reversal is associated with the origin, local growth, activation and further progression of the metastatic process. Consequently, NHE1 pharmaceutical inhibition by new and potent NHE1 inhibitors represents a potential and highly selective target in anticancer therapy. Cariporide, being one of the better studied specific and powerful NHE1 inhibitors, has proven to be well tolerated by humans in the cardiological context, however some side-effects, mainly related to drug accumulation and cerebrovascular complications were reported. Thus, cariporide could become a new, slightly toxic and effective anticancer agent in different human malignancies.

The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.

‘We can only cure what we can understand first’, said Otto H. Warburg, the 1931 Nobel laureate for his discovery on tumor metabolism. Unfortunately, we still don’t know too much the mechanisms underlying of cancer development and progression. One of the unsolved mystery includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg’s discovery, that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. One of the most mechanism to survive to the acidic tumor microenvironment are proton exchangers not allowing intracellular acidification through a continuous elimination of H(+) either outside the cells or within the internal vacuoles. This article wants to comment a translational process through which from the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed chemosensitizers as well, we have got to the clinical proof of concept that PPI may well be included in new anti-cancer strategies, and with a solid background and rationale.

Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment.

It is becoming increasingly acknowledged that tumorigenesis is not simply characterized by the accumulation of rapidly proliferating, genetically mutated cells. Microenvironmental biophysical factors like hypoxia and acidity dramatically condition cancer cells and act as selective forces for malignant cells, adapting through metabolic reprogramming towards aerobic glycolysis. Avoiding intracellular accumulation of lactic acid and protons, otherwise detrimental to cell survival is crucial for malignant cells to maintain cellular pH homeostasis. As a consequence of the upregulated expression and/or function of several pH-regulating systems, cancer cells display an alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe). Among the pH-regulating proteins, proton pumps play an important role in both drug-resistance and metastatic spread, thus representing a suitable therapeutic target. Proton pump inhibitors (PPI) have been reported as cytotoxic drugs active against several human tumor cells and preclinical data have prompted the investigation of PPI as anticancer agents in humans. This review will update the current knowledge on the antitumor activities of PPI and their potential applications.

Manipulation of the extracellular and/or intracellular pH of tumors may have considerable potential in cancer therapy. The extracellular space of most tumors is mildly acidic, owing to exuberant production of lactic acid. Aerobic glycolysis – attributable largely to chronic activation of hypoxia-inducible factor-1 (HIF-1) – as well as tumor hypoxia, are chiefly responsible for this phenomenon. Tumor acidity tends to correlate with cancer aggressiveness; in part, this reflects the ability of HIF-1 to promote invasiveness and angiogenesis. But there is growing evidence that extracellular acidity per se boosts the invasiveness and metastatic capacity of cancer cells; moreover, this acidity renders cancer cells relatively resistant to the high proportion of chemotherapeutic drugs that are mildly basic, and may impede immune rejection of tumors. Thus, practical strategies for raising the extracellular pH of tumors may have therapeutic utility. In rodents, oral administration of sodium bicarbonate can raise the extracellular pH of tumors, an effect associated with inhibition of metastasis and improved responsiveness to certain cytotoxic agents; clinical application of this strategy appears feasible. As an alternative approach, drugs that inhibit proton pumps in cancer cells may alleviate extracellular tumor acidity while lowering the intracellular pH of cancer cells; reduction of intracellular pH slows proliferation and promotes apoptosis in various cancer cell lines. Well-tolerated doses of the proton pump inhibitor esomeprazole have markedly impeded tumor growth and prolonged survival in nude mice implanted with a human melanoma. Finally, it may prove feasible to exploit the aerobic glycolysis of cancers in hyperacidification therapies; intense intracellular acidification of cancer cells achieved by induced hyperglycemia, concurrent administration of proton pump inhibitor drugs, and possibly dinitrophenol, may have the potential to kill cancer cells directly, or to potentiate their responsiveness to adjunctive measures. A similar strategy, but without proton pump inhibition, could be employed to maximize extracellular tumor acidity, enabling tumor-selective release of cytotoxic drugs encased in pH-sensitive nanoparticles.

The intratumor microenvironment is intrinsically acidic due mainly to accumulation of lactic acid as a result of increased aerobic and anaerobic glycolysis by the tumor cells. In general, the extracellular pH (pHe) in human tumors is below 7.0, whereas the intracellular pH (pHi) is maintained at neutral range, i.e., >7.0, by powerful pHi control mechanisms. The low pHe and the significant gradients between pHe and pHi affect markedly the response of tumors to various treatments such as chemotherapy, radiotherapy and hyperthermia. For instance, the acidic pHe increases the cellular uptake of weakly acidic drugs such as cyclophosphamide and cisplatin and thus increases the effect of the drugs, whereas the acidic pHe retards the uptake of weakly basic drug such as doxorubicin and vinblastine, thereby reducing the effect of the drugs. The radiationinduced apoptosis is suppressed by an acidic environment, whereas the hyperthermiainduced cell death is potentiated by an acidic environment. Better understanding of the control mechanisms of pHe and pHi in tumors may lead to device effective treatment strategy of human tumors.

Vacuolar H+-ATPase (V-ATPase) is a highly evolutionarily conserved enzyme, which is distributed within the plasma membranes and the membranes of some organelles such as endosome, lysosome and secretory vesicle. The mayor function of V-ATPase is to pump protons across the cell membrane to extracellular milieu or across the organelle membrane to intracellular compartments. V-ATPases located in cell surface act as important proton transporters that regulate the cytosolic pH to ~7.0 which is essential for most physiological processes, whereas V-ATPases within intracellular membrane are involved in cellular processes as receptor-mediated endocytosis, membrane trafficking, protein processing or degradation, and nutrients uptake (Nishi et al., 2002; Forgac et al., 2007; Toei et al., 2010; Cruciat et al., 2010). Malfunctioned V-ATPase is closely related to several diseases including tumor. More and more evidences indicate that V-ATPase is an enhancer for carcinogenesis and cancer progression, such as malignant transformation, growth and proliferation, invasion and metastasis, acquirement of multi-drug resistance, etc., which strongly supports that V-ATPase should be an effective target of anticancer strategy (Fais et al., 2007).

Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.

Cancer metabolism has received a substantial amount of interest over the past decade. The advances in analytical tools have, along with the rapid progress of cancer genomics, generated an increasingly complex understanding of metabolic reprogramming in cancer. As numerous connections between oncogenic signalling pathways and metabolic activities emerge, the importance of metabolic reprogramming in cancer is being increasingly recognized. The identification of metabolic weaknesses of cancer cells has been used to create strategies for treating cancer, but there are still challenges to be faced in bringing the drugs that target cancer metabolism to the clinic.

Melanoma cells in vivo maintain intracellular pH (pHi) in a viable range despite an extracellular tumor pH (pHe) that is typically below 7.0. In general, three families of transporters are capable of removing metabolic protons, but the specific transporters responsible for the maintenance of pHi at low pHe in melanomas have not been identified. Although the transporters exist in most cells, an inhibitor would be predicted to have selectivity for cells located in an acidic tumor bed because cells in that environment would be expected to have transporters chronically activated. In this report, the levels and extent of expression of the Na+/H+ exchanger (NHE-1) and two of the H+-linked monocarboxylate transporters (MCTs) were evaluated in three melanoma cell lines. The effects of inhibitors of each transporter were tested at an extracellular pH (pHe) of 7.3, 6.7, or 6.5 in melanoma cells that were grown at pHe 7.3 or 6.7. The activity of MCT isoform 1 (MCT-1) was up-regulated in three melanoma cell lines at low pHe, but that of NHE-1 was not. Furthermore, NHE-1 activity was lower in the melanomas than in other normal and malignant cell lines that were tested. Reverse transcription-PCR using primers specific for MCT-1, MCT-4, and NHE-1 showed that expression of none of these transporters was reproducibly up-regulated at the level of transcription when cells were grown at pHe 6.7 instead of pHe 7.3.Ex vivo experiments using DB-1 human melanoma xenografts grown in severe combined immunodeficient mice found that MCT-1 and not NHE-1 was a major determinant of DB-1 tumor cell pHi. Taken together, the data indicate that MCTs are major determinants of pH regulation in melanoma. In contrast, keratinocytes and melanocytes under low pHeconditions relied on NHE-1. Inhibitors of MCTs thus have great potential to improve the effectiveness of chemotherapeutic drugs that work best at low pHi, such as alkylating agents and platinum-containing compounds, and they should be selective for cells in an acidic tumor bed. In most tissues, it is proposed that the NHE-1 could compensate for an inhibited MCT to prevent acidification, but in melanoma cells this did not occur. Therefore, MCT inhibitors may be particularly effective against malignant melanoma.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as L-lactate. We previously reported that a-cyano-4- hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative controletreated cells. In this study, we demonstrated that MCT4 expression is associated with statininduced cytotoxicity.

One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

The pH gradient reversal can possibly be considered as the most distinct cancer specific event, occurring quite early. It is a mandatory event manifesting in all kinds of cancerous cells and tissues. It is essential for survival and proliferation of tumors. An alkaline, low salt diet with ample fruits and vegetables minimizes pH gradient reversal thereby reducing tumor aggressiveness and therapeutic resistance. This knowledge may be useful to replace the existing more toxic, non-selective therapies.

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.

Sodium bicarbonate combined with PD-1 or CTLA-4 Inhibitors or adoptive T-cell transfer reduces melanoma and pancreatic tumor growth. Cancer cells have the ability to grow in an acidic tumor environment that is detrimental to other cells, including immune cells. In a new article, researchers have reported that neutralizing the acidic tumor environment increases the efficacy of several immune-targeting cancer therapies.

One of the major obstacles to the successful treatment of cancer is the complex biology of solid tumour development. Although regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully investigated in the field of cancer. It has, however, been shown that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis. Hypoxic conditions are often observed during the development of solid tumours and lead to intracellular and extracellular acidosis. Cellular acidosis has been shown to be a trigger in the early phase of apoptosis and leads to activation of endonucleases inducing DNA fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells. Four major types of pH regulator have been identified: the proton pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter family (MCT). Here, we describe the structure and function of pH regulators expressed in tumour tissue. Understanding pH regulation in tumour cells may provide new ways of inducing tumour-specific apoptosis, thus aiding cancer chemotherapy.

Reprogramming of energy metabolism is one of the emerging hallmarks of cancer. Up-regulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus, targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here, we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient-derived pancreatic xenograft model. Lentiviruses expressing short hairpin RNAs (shRNAs) targeting 12 different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times, and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including carbonic anhydrase IX (CAIX), monocarboxylate transporter 4, and anionic amino acid transporter light chain, xc- system (xCT) were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation because shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient-derived pancreatic tumor model.

MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer.

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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Thanks for this remarkable article about the pH of tumor environment and your specific suggestions as to how to manipulate it. I am wondering about its relation to citric acid. How do these two paradigms (i.e.using e.g. sodium bicarbonate to alkalinize and using citric acid to prevent glycolysis) can be reconciled/used simultaneously?

Thank you. If we target glyco inhibition with Citric Acid and create a more alkaline environment with Sodium Bic the two will work well together as they would have different mechanism against cancer. What I do not know is if Sodium Bic would interfere with the availability of Citric Acid at the tumor site. On the other hand, if we believe that another mechanism through which Acids can work against cancer is by further lowering the extra cellular pH, Sodium Bic should be avoided as it works against that. All in all, I would probably not combine Sodium Bic with Citric Acid, just to be on the safe side due to above potential interactions.
This is how I understand it Helga. I hope it answers your question.

Thanks for your response. I was inclined to also avoid sodium bicarbonate for now. As I said on the citric acid thread, I found some omeprazole at home and took one. Now am going into the infra sauna to work up some sweat.

I answered your question about the Omeprazole dose in another place but just to make sure we have the answer also on this pH related page, I will post the comment here too. This is just to have a feeling on the dose that has been seen effective against cancer when given with chemo:

First, I should say Lanzoprazole seems to be more effective than Omeprazole (I will later search for the reference). Next, here is a very relevant study performed on dogs showing how the administration of high dose Lanzoprazole next to Chemo lead to extreme increase of chemo effectiveness (partial or complete responses in 67.6% cases using Lanzoprazole, vs. 17% who experienced only short lived partial responses in the control group): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264547/ In this case they used 5mg/kg/day during 3 days, followed by four days at the dose of 1 mg/Kg/day to prevent gastric hyperacidity rebound.

That is a good question Emad. I think it will be not so difficult to find your answers if you do a bit of research on that. If you find more info please post it here too. I am sure there are many studies on the safety of Omeprazole and Lanzoprazole. For example, just a quick search indicates the following for a specific disease: “The recommended initial dose is 60 mg once daily. The dose should be individually adjusted and the treatment should be continued for as long as necessary. Daily doses of up to 180 mg have been used. If the required daily dose exceeds 120 mg, it should be given in two divided doses.” https://www.medicines.org.uk/emc/medicine/24998

Yes, real life. Unfortunately nab-paclitaxel was too expensive for a long term option (400 mg per month was about 1700 euros) and metronomic plus omeprazole wasn’t initially clear if working (without celecoxib and omeprazole it didn’t).

I am sorry to hear the financial limitations were the reason not to be able to continue with a treatment that was showing results. I think this is a very valuable piece of information. Can you please explain what was the tumor type, the treatment used and how that was used (e.g. timing, dose) and the observed results? Thanks in advance.

That happened over 4 years ago, so some details may be inaccurate. The cancer type was metastatic NSCLC that became refractory to Carboplatin and Taxol or Carboplatin and Vinorelbine. Keep in mind that a lot of new articles were published since, I didn’t have today’s knowledge.
IIRC the lansoprazole was given as a pre-treatment before the Carboplatin (every 3 weeks, probably useless by that time), and Abraxane weekly. Progress was measured by weekly blood test, evolution of the CEA marker.
The best response was about 10% reduction in CEA weekly when the high dose lansoprazole was given before the Abraxane (each week). But the oncologist believed that the cancer became sensitive again to paclitaxel (which proved wrong) and my father was approved to be given Erlotinib (which turned out a disaster), paid by the insurance. I could have afforded to pay for another couple of months of Abraxane, but my father didn’t want me to.

IIRC the high dose was 120 mg the morning before the chemo (which usually was late evening) and then 30 mg daily for a couple of days after.
Also IIRC the best reduction in CEA was when the chemo was delayed for a day and there were 2 days of 120 mg before Abraxane (suboptimal dose 100 mg, optimal should have been 140 mg).
My idea was to have get the cytotoxic result from Carboplatin (pre-treated with lansoprazole) and then the next 3 weeks to stall the cancer with Abraxane.
It turned out the best results were from Abraxane + lansoprazole instead, by then resistance to Carboplatin was too high.
A couple of years later I found this: Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanomahttps://www.ncbi.nlm.nih.gov/pubmed/25449440

Thank you Ovidiu! This is very clear and helpful for many.
I always had a very good feeling regarding this strategy. Adding more proton pump inhibitors (such as Amiloride) next to Lanzoprazole should further help Chemo or Radiation.

I don’t know for how long the high dose lansoprazole can be taken. Before giving it to my father I tested it on myself and there was some nausea / uneasy feeling.
Also PPIs and cimetidine shouldn’t be used with erlotinib (this was not the case for my father).
Gastric Acid suppression is associated with decreased erlotinib efficacy in non-small-cell lung cancer.https://www.ncbi.nlm.nih.gov/pubmed/25246385

Ovidiu, i understand you and your father are fighting Lung Cancer?
If so me and my mother are fighting it too. Some advice or guidance from your own experience would be much appreciated. I am kinda new here and apparently don’t have as much knoledge as you do.
My mother is against chemo due to the belief that it will only cause more harm than good.

@Alex: my father died in December 2012, the knowledge I accumulated trying to help him didn’t make much difference.
As for advice for your mother, please first post some info on the cancer type. Is it NSCLC or other kind? Is she a smoker? Did you perform tests on the resected tumor to determine the onco-protein(s) involved (like EGFR, HER2, KRas, ALK)? Is the metastasis still limited to the lung(s) or has spread to lymph nodes and other organs (this is visible on a CT scan)?

The issue of Seminars in Biology in which D’s recent article appeared also had this.
Very interesting, very focused acidification of tumor cells resulting in tumor clearance.
Focal photodynamic intracellular acidiﬁcation as a cancer therapeutic, Semin Cancer Biol (2017)

Is this body ph even a thing? What about stomach acid? It all sounds cute and great, a little baking soda, some salt…. magic bullet….
No disrespect but, it’s confusing for me and probably the vast majority of people
Then there’s the other side claiming that the body can not and should not be alkaline, that in fact the body constantly invests energy to keep ph levels as they are.

PS, was watching a video on natural remedies and got cut by radiation therapy commercial….. big business!
I’ll leave that to your private opinion, mine if you should ask is…. not good.

Body pH is a fact and unbalanced pH within the tumor cells and around the tumors are just facts. There is no question about that as there is a huge amount of science supporting that. Nobody in academic world is questioning that.

What is indeed questionable is the alkaline diet or baking soda promoted as the cancer cure.

Personally, I like the alkaline diet not because of its name but because of the healthy components of this diet. Just that.
Regarding backing soda, I do not know what is really the effectiveness and impact of that on the body pH. What I know, is that when administered IV, the impact can be relatively large on the pH and may also affect the pH around the tumors which would be positive for e.g. immune system, due to the way how T cells, DC, macrophages and other immune cells are activated and impacted by pH. However, I have a bit of strange feeling regarding IV bicarbonate to achieve pH modulation around the tumor and I do like and believe much more in the effectiveness of the strategy discussed above.

Thank you dear Daniel.
Good news here. DCA Arrived today, Mom is feeling better.
Still didn’t give mom any DCA, and eased down on metformin.
I would like to know what is your starting dosage recomendation for DCA and if we should stop to 1g/day or more if possible.
Also 1g/day in one dose or spread in 2.
Blood tests performed before this recent treatment are showing a slight increase in markers and some decreases in the chemistry part.
CEA 46.74 – out of range
CA 19-9 20.2 – still in range

If i remember correctly, Simoncini did not promote the idea of ingesting of baking soda but did promote the IV or tumor injection or baking soda.
I also agree with the nutritional value of the “alkaline diet” but not with the goal of getting the body “alkaline”
As for achieving ph levels in the blood hostile to tumors. i’m under the asumtion that the mechanism of action was more oriented towards osmosis of tumor tissue liquids.
I could all be wrong about all this, if so, i am sorry for wasting time.
A few things i would like to ask is what about vitamin k? There are many documented cases of “spontaneous” remission. I’m wondering if clotting of vital blood veins would have a possible role there. And if so, as with snake venom, would it make sense to try something like that? I understand there could be serious consequences. But the tumour itself sounds like it would make it easy since the blood around it is thicker than normal from what i understand, in theory, making it easy and less risky.
Just exploring some ideas and thoughts, nothing more.
All this reading got me seeing that the immune system can’t really tell there’s something very dangerous there, not enough to launch a full attack and then begin to eat at it, a trigger may be needed….
It can’t see that the tumor is non-self because the tumor is very very very similar to self, i know there’s a lot to talk about there if you get into technicals but i won’t and i can’t. Sorry for my lack of knoledge but i try. Don’t wish to sound arogant or ignorant.
I come humble and willing to learn within the limits of my understanding.
My questions can be silly sometimes but i feel that questions also add value to what we are trying to do.
I’ve been offered a possible chance to have a vaccine done from a tumor sample taken trough puncture. I don’t know weather this would help in reality or not, this is when your vast experience comes in play again. I know in theory things work nice and perfect, but you are more aware of the reality of these treatments.

Thank you for doing all this for all of us, i am sure Mihaela would be proud, and i hope your mother knows how lucky she is to have given birth to such a great man who is trying to solve the world’s most problematic medical issue.
Have a good evening,
Alex & Mother.

you don’t want to “clot” the veins as that clot might travel to unwanted regions of the body and cause embolism. What you want to do instead is anti-angiogenesis, i.e. cut off the blood supply of the tumors. If you type in google “anti-angiogenesis natural products” you’ll get many hits and a list up front:
4.1 Herbs and Phytochemicals
4.1.1 Artemisia annua (Chinese Wormwood) …
4.1.2 Viscum album (European Mistletoe) …
4.1.3 Curcuma longa (Curcumin) …
4.1.4 Scutellaria baicalensis (Chinese Skullcap) …
4.1.5 Resveratrol and Proanthocyanidin (Grape Seed Extract) …
4.1.6 Magnolia officinalis (Chinese Magnolia Tree)
More items…https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1891166/

Also, regarding the immune system, sy said (maybe Alberto) that lactic acid suppresses the immune system. That is one reason to consume citric acid because it suppresses fermentation and therefore production of lactic acid. This in itself is beneficial for the immune system.

As always,
Thank you so much Helga.
You may notice i come back to these late, yes i’ve ben very very very busy and will continue to be sadly. But i am making progress.
Please let me know if you would like any help with anything you may not find in your area as i live in Romania and some things can be found cheaper here depending on many factors. I also have technical skills when it comes to computers and some other appliances.
As a friend i offer my help when needed.
Always Available on Skype Snake_Systems

Dear Helga,
Music was my first love and that lead to me learning english sincer kindergarden, i admit i am not what i used to be when it comes to both. Growing up to be an adult man has it’s “side-effects”. And you kinda loose skills, lack of practice, interest,
Because of music i learned some basic electronics to make things sound louder of apply filters to the sound, mix it.
Meanwhile i discovered the computer in it’s relatively primitive form, tape storage, keyboard, tv screen, old stuff. Even then
This must have been in the early 90’s. And i took interest in the computers due to their ability to play sounds.
Also as a kid i was also interested in playing those games i could get my hands on,
Over time despite the limited financial restrictions, i’ve learned how to fix computers and in my 20’s i wanted to get my own IT company going since i was so successful as a freelancer and have accumulated a lot of reputation till 2008.
Destiny has made so that the recession also came then, along with people’s drop in interest for PC’s and switching to mobile.
I couldn’t get money from a bank and even if i did, the market was dropping fast.
Had some jobs but they didn’t last much sadly. Life always hit me hard from all sides, i’m in a village, i like it here now.
But it’s not what i wanted and expected from me and life. I should have been running a great IT company called Snake Systems…. who knows…. one day.
Nowadays i’m a university student, and i work at home in a virtual world called Second Life where virtual currency can be converted into real currency $.
This virtual world offers plenty of business options, selling virtual land, services, others. My computer skills are useful there and not just that. It’s a matter of using your own imagination to come up with profit.
Income wise it’s not much, it used to be enough for me, before this cancer.
I work there because i have no actual alternatives, especially now when i rather be with mom than to commute to some job at the supermarket in the city where they would let me go in 2 months, as they do with so many.
As for the student part, being 32, knowing you gave up on so many things in the past in the name of love, looking back and seeing those wrong choices, i wanna prove to everyone else around me i am not stupid or uneducated and that it’s never too late to do it., i just made the wrong choices for things i thought were more important to me at that time.
I don’t want to be underestimated just because i lack a degree. I am more than just a paper, but if the paper will prove it. I will have it. And when i get it i will make multiple copies to share with everyone who has underestimated me in that matter. Company owners, former co-workers, “friends”, former girlfriends who would mock me, relatives.
And yet again i am being dumped by the gf, when you have problems, the people who say that they love you, may show that they don’t understand anything and they rather not deal with your problems and they leave. Despite the “i love you”.
Single 4 life LOL… rather be single than to live a life full of deception.
What can i say…. i think this answers your questions 🙂 more or less.
Do take care please.
Alex

Thank you,
I hope that i can get my mom feeling well and then we can all look back and laugh, having learned a lot so that maybe we too can help others in need and willing to receive the help and fight the fight, ready to succeed but also fail.
There is nothing i dream more than this now
Thank you very much for everything.
Alex

Thank you for the very good question. I do not have a clear answer for Ibuprofen dosage required to inhibit MCT4 but I have an answer for others NSAIDs dosage require to inhibit MCT1.
This however can give us an idea if the typical NSAIDs and their typical dosage is close of far from MCT inhibition, and the answer is a nice one, i.e. typical dosage of NSAIDs is effective in inhibiting MCTs.
I am happy you asked this question because as a result, I found this great reference stating the following:

“The inhibitory concentrations of tested NSAIDs (diflunisal, mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid) are in the range of physiologically relevant concentrations that are achievable from the oral intake. For example, the suggested dosage range of diflunisal is 500 mg to 1000 mg daily for osteoarthritis and rheumatoid arthritis. The peak plasma concentration of diflunisal achievable from single 500 mg oral dose was 87 ug/mL, while the Ki of diflunisal is 29.56 uM (equivalent to 7.40 ug/mL). Therefore, a strong inhibition of NSAIDs on MCT1 is achievable at the relevant plasma concentrations of diflunisal.

Three NSAIDs, namely diclofenac, meclofenamic acid and tolfenamic acid exhibited strong inhibitory effects on L-lactate transport, with a Ki value of 6.17 uM (~1.96 ug/mL), 9.97 uM (~ 3.35 ug/mL) and 8.95 uM (~ 2.34 ug/mL), respectively. The recommended dosage for diclofenac is 100-150 mg/day in divided doses for the relief of osteoarthritis. The peak plasma concentration of diclofenac achievable from single oral 50 mg dose is 0.8 ug/mL, while the peak plasma level of diclofenac achievable from multiple doses (oral 50 mg was administered 3 times daily for 7 days) was 2.3 ug/mL [218]. The recommended dosage of meclofenamate sodium for pain relief, arthritis and osteoarthritis is 200 to 400 mg daily, administered in three or four equal doses. After the administration of 100 mg meclofenamate sodium for 18 days every 8 hours, the peak concentration was 4.8 ug/mL for the parent compound on both day 1 and day 18. Lastly, tolfenamate is subscribed to patients suffering from acute migraine with a recommended dosage of 200mg. Pharmocokinetics data shows that a single oral dose of 200 mg, 400 mg and 800 mg of tolfenamic acid achieved a peak concentration of 2.97 ug/mL, 6.15 ug/mL and 12.2 ug/mL in the plasma, respectively [219]. Taking this data together, it suggests that strong inhibition of NSAIDs on L-lactate transport on human erythrocyte is expected at the therapeutically relevant plasma concentrations of tested NSAIDs.” http://scholarbank.nus.sg/bitstream/handle/10635/35743/LeanCB.pdf?sequence=1

Thanks Daniel, that’s good news.
I am glad that I can be to some help sometimes to 😉 sometimes a simple question can open up new line of thoughts.
Anyway maybe diclofenac is a better choice than ibuprofen.

Yes one can be lucky to find the right substance, for example I have read that one person with pancreatic cancer did control it with only curcumin and gemcitabine, for at least 18 month, which is very long time with this aggressive cancer. Every tumor is unique.
I also believe to find the right synergies between different substances. I believe it’s harder for the cancer to become resistant if it’s attacked in different ways.

Very impressive.
I’m borrowing a theory that one of the main reasons some treatments may not work when they work for others.
That theory is based on autoimmune disease. An imbalance of the immune system that likely allowed the cancer to form in the first place and that some treatments may actually favor the wrong side of the immune system, the one that is already at nominal levels. This is where chemo would possibly help, but then again i feel a more smart solution should and must exist.

Well i watched a video a while back, from a non-doctor.
He was saying that the Gerson may actually do the cancer a favor. That it’s important to check glands, liver, cell counts etc. To do more and more tests to determine the right treatment.
Same would go for any other protocol, that whatever worked for someone, will possibly fail for another or do worse due to autoimmunity.
He was saying that there is no CURE because cancer has too many starting points as options and so many routes, that it ends up being something else even from the start.
He was saying we know a lot about cancer but we’re not making the treatment a per/person thing.
Indeed there seems to be a rush like the line in a supermarket… very very little special individual treatment.
We seek the fast, easy, cheap solution with the most profit. I’m all too sure you know about all that.
I’m thinking that maybe mother has an autoimmune disease. She had abnormal bone growth in her knees, a year before diagnosis, this lead her to believe it may be a similar problem in her back, but it wasn’t…….

Hello Alex
Yes tricky question, as a layman what I’ve understand is that ALS, MS and common allergia, is autoimmune deseases. That the immune system is somehow overactive and sometimes attacking the body’s own tissues.
About allergia I have heard conflicting reports that people with allergia have lesser incidents of cancer due to the overactive immune system. But I have also heard the opposite.
Personally I have come to like the explanation that inflammation cause some cancers, this is maybe not contradicts your theory, at least inflammation seems to be a strong driving force.
Anyway the cause of cancer starts a chain of failures in the body and it can be hard to indentify the root cause. One can perhaps just look on one chain on event believing it’s the cause of the cancer.

I actually started to read your article above and must say again, really impressed! Have you published this actually in a journal (or was that something else, someone seemed to say you published an article in a journal)? This is brilliantly thematic and well-thought-up about various aspects of the pH around and in the tumor. I haven’t finished it reading yet. So it seems there are quite a few drugs that are/can be repurposed as cancer treatments. What I found scary was the story about the amiloride and ovarian cancer http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-2362.pdf

They found a metastasis in the leg muscle of the patient?! Never heard of such a thing. Anyway, I encourage others as well to take their time and read this article. It is simply brilliant!

Thank you very much for the appreciation. I also very much like this strategy. And what is interesting is to see that this perspective (pH modulation) captures a large of the drugs that are known to work against cancer. So this may be a central mechanism while the other mechanisms identified on the same drugs may just be a result of pH modulation (which is known to lead to various intracellular enzyme inhibition or activation, etc.). I will send to you the PDF of the article by e-mail.

Amiloride is really interesting.Because of my poor language,i searched it in my own language.
It says it is used for edema which the cause of hypertension,low pumping heart or liver cirrhosis.
It protects potassium so we should be VERY careful.
But you are right ,it deserves more searching.

regarding repurposed drugs to fight cancer you can also check what drugs Ben Williams used to beat terminal glioblastoma.
Since then others with GB used similar cocktails with success. these are drugs againts asthma, ace, hearburtn… all pretty boring stuff. Again, i dont think most oncologists are aware of his approach (or care about) and they dont propose this – totally safe- method for terminally ill brain cancer patients with no chance to survive.

Even B Williams remembers that one of his drugs told him he could hurt himself with these drugs.. then the doctor started to laugh and apologised.

Of course this evidence is anecdotical, HOWEVER, almost each drug in the cocktail has demonstrated anti cancer potential so in this context i am sure Ben W and his followers would not be here without the cocktail.

I was not aiming for publishing in scientific journal, but my focus was always on finding ways to help my dear wife. IN that context I came in contact with the authors, who are both great scientists, doctors and great humans at the same time. We exchanged ideas, we resonated and they asked if I like to join in writing the review. That is the story on short behind that very nice review. More valuable than being part of the team writing the review is that I feel honored to maintain the contact with the authors who have a long history in the battle against cancer. I hope I can intensify that once I will be able to allocate more time to the oncology field. I will also response asap to your e-mail – it has a star on it as a reminder to respond 🙂
We can also explore the options to use our network in creating scientific content by connecting the existing scientific work to gain new perspectives.

My friend has problems with acid reflux since 2000’s.She has been using lansoprazole 30 mg/day But modest effect.
Than she found Esomeprazole.
It has better effect on stomach acid which she experienced in real life.
May be it is better than lansoprazole on also proton pump inhibition of cancer cells.
Do we have any data on that?
And i couldnt find cimeditine,it is out of production.Do we have any similar drug?
Thanks
Kind Regards
Ergin

Dear Ergin,
Based on extensive research from Italy, Lansoprazole seems to be the most effective. I have to find the reference but I also receive that via private communications from the researchers.
Cimetidine is available on e-bay as is an over the counter drug in USA (Tagamed) and in Asia. In Germany you can get it from pharmacy but on prescription from your doctor.
Kind regards,
Daniel

I called her and learned that Esomeprazole is 40 mg tablets.Lansoprazole is 30mg.
Small difference but big result in stomach acid inhibition.And may be after 16 years lansoprazole became resistant.
Just an idea,can we use both before chemo?
Kind Regards
Ergin

High potassium may also be an issue and fuel the tumors as well as sodium. In addition I would not use bicarbonate as long term strategy but only as IV before immunotherapy or chemotherapy (if chemo is weak base which seems to be common for many chemo). Evidence is building up suggesting that tumor may grow faster in an alkaline environment compared to acidic one. As a result, I think long term administration of sodium bicarbonate or other forms, may be the wrong approach, specifically when the tumors are large. Unfortunately, that is my conclusion at this point. I am saying unfortunately, because I did believed and would like to believe in sodium bic benefits.

I’m not 100% if this would translate to carboplatin as the two have pretty different chemical compositions. The main similarity is the two NH3 groups bonding to the Pt. Apart from this, cisplatin has just two chlorine molecules bonded to it, while carboplatin is more complex.

Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O 2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth.

Guys I am completely agree about the importance of pH in cancer progession. Here we are talking about different ways to alkalinise the body. But let me tell you something the best way to do is with a machine called kagen, you can clean your food and also drink water continuosly with a pH of 11, this pH water is similar to Lourdes water where a lot miracles happen you are giving to your body also electrons to regulizar membrane cells

Thanks for the comment.
The above post is focused on ways to induce the accumulation of acidity inside the cancer cells. This can lead to cancer cell death. The “side effect” is that the body becomes more alkaline, which is also good for the immune system and others. Alkalinity of the body can indeed be achieved in multiple ways but I think this approach alone has potential only for early cancers or small tumors. For advanced cancers, when tumors are larger on the other hand I expect inducing alkalinity of the body with diet or water will only have limited impact on the tumors. This is why, for advanced cancers I would turn my attention to proton pump inhibitors and other ways to increase the intra cellular acidity, which is a more aggressive approach.

If we only want to focus on alaklinity of the body for advanced cancers, we may consider Sodium Bicarbonate. But to my knowledge in some cases that may also lead to growth of the tumors so I would only used it prior to immunotheraphy or weak base chemotherapy.

I read an article about how to potantiate antibiotic effectiveness with proton pump inhibitors.

The real war is begining Alex.If i can not do my duty,i wont forgive myself.I need all help from now on.Help for thinking logically.We already know lots of mechanisms by Daniel’s help.I have no computer here,so skype.

Hi Daniel- I wanted to thank you for this very complete and practical article. We are actually familiar with the Advanced Medical Therapeutics clinic you mention above as it is a short drive up the road from us. We did visit with the doctor who runs it and found him to be both compassionate and brilliant. Ultimately we decided not to work with him for the moment as my husband is in NED and, with my medical background (Naturopathic Physician), we are able to do many therapies and use many medications ourselves. However, we would definitely consider using his services if we need to in the future. I believe he also works to some extent with Dr. Jason Williams and does work with 3BP combined with Salinomycin in Columbia. Anyhow, the information in this article is going in my “just in case” folder as it is good to have a variety of different strategies when and if we need them.

(husband has stage IV prostate cancer, currently in NED with androgen deprivation)