The power of metabolic targeting and ROS manipulation in cancer treatment

In pivotal research published in 2004 and again in 2023, many contemporary cancer drugs were found to have little impact on enhancing the quality of life or prolonging the lives of those with metastatic cancer (click here and here). Metastatic cancer is often associated with reduced survival rates because alternative approaches are limited when cancer cells evolve and acquire multi-drug resistance. Therefore, there is a dire need to develop new treatment methods. Fortunately, research scientists and forward-thinking physicians are constantly looking for new ways to fight cancer, including using diet and lifestyle (click here). 

Thomas Seyfried, PhD, professor of biology, genetics, and biochemistry at Boston College has coined the term “press/pulse,” referring to an innovative strategy for treating cancer based on its metabolic vulnerabilities. It is a two-step approach that combines these two distinct phases:

1. Press: This aspect involves weakening cancer cells by inducing and maintaining a state of energy stress by “starving” the cells of essential fuels, including glucose, glutamine, and fatty acids.
2. Pulse: This part aims to kill the already-stressed cancer cells by subjecting them to potent and intermittent waves of cellular damage. These “pulses” can be chemotherapy, radiotherapy, and other pro-oxidative treatments that induce lethal damage to critical cellular structures.

Here are some of the key advantages of this approach:

1. Reducing drug resistance: One of the major challenges in cancer treatment is the development of drug resistance. The press/pulse approach may help in this regard by continuously keeping cancer cells under metabolic stress and then hitting them with high-dose treatments before they can adapt or develop resistance.
2. Minimizing side effects: By using lower doses in the press phase, this approach can potentially reduce the side effects typically associated with high-dose chemotherapy or radiation therapy. This can improve the quality of life for patients during treatment.
3. Synergistic effects: Combining different treatment modalities in a coordinated press/pulse manner can have synergistic effects, where the combined effect is greater than the sum of the individual treatments. This can lead to more effective cancer cell killing.
4. Potential in treating various cancer types: Preliminary studies suggest that the press/pulse approach could be effective against a variety of cancer types, especially those that have shown resistance to traditional treatments.
5. Focus on cancer stem cells: This approach might be particularly effective against cancer stem cells, which are often resistant to conventional therapies and are thought to be responsible for cancer recurrence and metastasis.

STEP 1: Targeting Cancer Metabolism

Weakening cancer cells by impairing glucose, glutamine, and fatty acid metabolism present several advantages in cancer treatment:

1. Exploiting tumor dependence on altered metabolism: Cancer cells undergo metabolic rewiring, becoming addicted to specific fuels due to mutations and epigenetic changes. They often heavily rely on glucose and glutamine for energy (via aerobic glycolysis and glutaminolysis), even in the presence of oxygen (the Warburg effect). Limiting these fuels starves the cancer cells, hindering their growth and proliferation.
2. Targeting a fundamental vulnerability: Targeting energy metabolism bypasses the traditional focus on specific mutations or signaling pathways, which can be diverse and evolve through resistance. This approach attacks a core and fundamental vulnerability shared by many cancer types, increasing its potential for broad applicability.
3. Enhancing sensitivity to other therapies: Chronically stressed cancer cells become more susceptible to pro-oxidative treatments like chemotherapy or radiation. This “priming” effect can significantly boost the effectiveness of existing therapies, potentially requiring lower doses and reducing side effects.
4. Selective targeting of cancer cells: Healthy cells have greater metabolic flexibility and can adapt to fuel scarcity by utilizing alternative sources like ketone bodies. This differential dependence provides a therapeutic window, reducing harm to healthy tissues and potentially minimizing side effects.
5. Overcoming resistance: Unlike traditional therapies that target specific mutations, which can be lost, metabolic stress can be maintained, making it harder for cancer cells to develop resistance. This could lead to more durable therapeutic responses.
6. Synergistic effects with other interventions: Combining metabolic stress with other strategies like ketogenic diets, metabolic inhibitors, or hypoxia therapy can create a potent, multi-pronged attack, further weakening and eliminating cancer cells.
7. Potential for personalized medicine: Understanding the specific metabolic dependencies of different cancers can enable personalized treatment plans, tailoring fuel restriction strategies to specific tumor types and vulnerabilities.

To induce metabolic stress in cancer cells, we use a combination of these medications and administer them on a continuous/ongoing (i.e., “press”) basis:

1. Syrosingopine
2. Diclofenac
3. Simvastatin
4. Metformin

The above medications work in concert to cut off the energy supply to cancer cells. Cancer cells need a lot of energy to grow and spread. They rely on a molecule called NAD+ (oxidized nicotinamide adenine dinucleotide) to turn nutrients into ATP (adenosine triphosphate)—the primary energy molecule needed for cellular functions. Syrosingopine, diclofenac, simvastatin, and metformin prevent the regeneration of NAD+, but in two different ways:

1. Syrosingopine, diclofenac, and simvastatin together block the two most important lactate transporters, MCT1 and MCT4, thereby inhibiting lactate export. High intracellular lactate concentrations, in turn, prevent NADH (reduced nicotinamide adenine dinucleotide) from being recycled into NAD+.
2. Metformin blocks the second of the two cellular pathways that help NAD+ regenerate.

Cancer cells have an insatiable appetite for energy, requiring an uninterrupted supply of NAD+ for several crucial processes that support their relentless proliferation and ability to avoid cell death. When NADH can no longer be recycled into NAD+, it creates an energy shortage. A cancer cell depleted of NAD+ will experience disruptions in its ability to metabolize glucose, glutamine, and fatty acids, thereby compromising its survival and potentially making it more vulnerable to pro-oxidative therapies. Here is a breakdown of the potential effects:

Glucose metabolism:

• Reduced glycolysis: NAD+ is essential for activating key enzymes in glycolysis, the process by which cancer cells ferment glucose into lactate even in the presence of oxygen (Warburg effect). Without sufficient NAD+, glycolytic flux would be hampered, limiting the cell’s ability to generate ATP and reducing its capacity for rapid proliferation.
• Impaired lactate secretion: NAD+ is also involved in lactate dehydrogenase, the enzyme responsible for converting pyruvate (generated during glycolysis) into lactate. Depletion of NAD+ would hinder lactate production, potentially leading to intracellular acid build-up and further metabolic stress.

Glutamine metabolism:

• Decreased glutaminolysis: Glutamine is another major fuel source for cancer cells. NAD+ activates enzymes involved in glutaminolysis, a process that converts glutamine into glutamate and then fuels the tricarboxylic acid cycle (TCA cycle) for energy production. With limited NAD+, glutaminolysis would be hindered, depriving the cell of an important energy source and metabolic building block.
• Dysfunctional glutathione synthesis: Glutamine also serves as a precursor for glutathione synthesis, a key antioxidant involved in stress resistance. NAD+ depletion would impair this process, further weakening the cell’s defense against oxidative stress.

Fatty acid metabolism:

• Disrupted β-oxidation: NAD+ is involved in key steps of β-oxidation, the process by which fatty acids are broken down for energy. Depletion of NAD+ would disrupt this pathway, limiting the cell’s ability to utilize fatty acids as an alternative fuel source.
• Reduced membrane biosynthesis: Fatty acids are also crucial for building and maintaining cell membranes. With impaired β-oxidation, the cell might struggle to synthesize new membranes, hindering growth and potentially compromising its integrity.

A cancer cell depleted of NAD+ would not only experience significant disruptions in its ability to metabolize glucose, glutamine, and fatty acids, but it would also experience a significantly reduced ability to withstand excessive oxidative stress, making it more vulnerable to irreparable damage and subsequent death. Here’s why:

Importance of NAD+ in resisting oxidative stress:

• Production of defensive antioxidants: NAD+ is needed to produce glutathione, thioredoxin, superoxide dismutase, and catalase. These crucial antioxidant molecules play a vital role in protecting cancer cells from oxidative stress.
• NADPH, a reduced form of NAD+, is a crucial cofactor for glutathione reductase, an enzyme that maintains glutathione in its reduced state (GSH). GSH is a key antioxidant that scavenges reactive oxygen species (ROS), the major culprits of oxidative stress. Without sufficient NAD+, NADPH production dwindles, leading to decreased GSH levels and weakened antioxidant defenses.
• NAD+ activates sirtuins: Sirtuins are a family of proteins involved in stress resistance and DNA repair. They require NAD+ as a substrate for their activity. Depleting NAD+ would impair sirtuin function, hampering the cell’s ability to repair oxidative damage to DNA and other critical molecules.
• NAD+ regulates energy metabolism: Cancer cells often rely on aerobic glycolysis for energy, even in the presence of oxygen. This process, known as the Warburg effect, generates ROS as a byproduct. NAD+ depletion can disbalance energy metabolism, further increasing ROS production and exacerbating oxidative stress.

When the lactate transporters of cancer cells are blocked with syrosingopine, diclofenac, and simvastatin, inhibiting lactate export may have significant effects on the anti-tumor immune response. Lactate, a byproduct of cancer cell metabolism, plays a critical role in the tumor microenvironment. Here is an overview of the impact:

1. Altered tumor microenvironment: Cancer cells typically undergo a metabolic shift towards glycolysis, producing lactate even in the presence of oxygen (Warburg effect). Lactate export is crucial for maintaining this metabolic phenotype. When lactate export is blocked, it leads to an accumulation of lactate within the cancer cells, potentially disrupting their metabolic processes.
2. Enhanced immune response: High levels of lactate in the tumor microenvironment are known to suppress the immune system, particularly affecting T-cells and natural killer cells, which are critical for the anti-tumor response. By blocking lactate export, the suppressive environment might be reduced, potentially allowing for a more robust immune response against the tumor.
3. Activation of immune cells: Accumulated lactate can inhibit the function of immune cells. When lactate export is blocked, it might alleviate this inhibition, thereby restoring the function of immune cells, such as cytotoxic T lymphocytes and dendritic cells, enhancing their ability to fight the tumor.
4. Reduced immunosuppression: Cancer-derived lactate contributes to the creation of an immunosuppressive microenvironment. Blocking lactate export could hinder the ability of cancer cells to evade the immune system, making them more susceptible to immune-mediated destruction.
5. Potential for improved immunotherapy: This approach might complement immunotherapies by reducing the immunosuppressive environment, making immunotherapies more effective.
6. Impact on cancer progression and metastasis: Lactate is also involved in promoting angiogenesis (the formation of new blood vessels), which is essential for tumor growth and metastasis. Blocking lactate export could potentially slow down these processes.

Overall, the potential consequences of NAD+ depletion and inhibition of lactate export for cancer cells using syrosingopine, diclofenac, simvastatin, and metformin include:

• Increased sensitivity to ROS-induced damage: With weakened antioxidant defenses, DNA, proteins, and lipids within the cell become more susceptible to ROS-mediated damage. This can lead to mutations, disrupted cellular processes, and ultimately cell death.
• Reduced capacity for DNA repair: Impaired sirtuin function hinders the cell’s ability to repair oxidative DNA damage, potentially promoting genomic instability and tumor progression.
• Enhanced susceptibility to chemotherapeutic drugs and other ROS-inducing therapies: Many chemotherapy drugs work by inducing oxidative stress in cancer cells. NAD+ depletion could sensitize cancer cells to these drugs, making them more effective and potentially reducing side effects on healthy cells.
• Improved immune responses against the tumor: Activation of key immune cells, reduced immunosuppression, and potential improvement in immunotherapy effectiveness. Additionally, it may slow cancer progression and metastasis by affecting lactate’s role in angiogenesis.

STEP 2: ROS manipulation

Manipulating reactive oxygen species (ROS) levels in tumors by using ROS-generating therapy to induce excessive oxidative stress, is a proven method for killing cancer cells. Here is why and how it works:

1. Cancer cells have elevated ROS levels: Cancer cells often have higher levels of ROS compared to normal cells due to their rapid proliferation and altered metabolism. While they develop mechanisms to survive this oxidative stress, they are also more vulnerable to further oxidative damage. By amplifying ROS levels, cancer cells are pushed beyond their survival threshold, leading to cell death.
2. ROS can damage vital components: Increasing ROS levels to toxic levels and exhausting cancer’s antioxidant systems can cause irreparable damage to DNA, proteins, lipids, and mitochondria, and disrupt essential cellular processes, leading to cell death.
3. Selectively targets cancer cells: Healthy cells have better antioxidant defenses and can manage moderate ROS increases. Targeting ROS exploits the inherent vulnerability of cancer cells, minimizing harm to healthy tissues.
4. Stimulation of immune response: High levels of ROS can lead to increased presentation of tumor-associated antigens (TAAs) and stimulation of an immune response, regulate the infiltration and differentiation of immune cells, manipulate the expression of immune checkpoints, and change the tumor immune microenvironment. This can make tumor cells more recognizable and attackable by the immune system. When used in combination with immunotherapy or hyperthermia, amplifying ROS could potentially improve the recognition and destruction of cancer cells.
5. Targeting cancer stem cells: Cancer stem cells are a subpopulation within tumors that can drive metastasis and cancer recurrence. They are usually resistant to conventional therapies. Increasing ROS may specifically target these cells, which are believed to have lower antioxidant capacities compared to the bulk tumor cells.

To induce cytotoxic (lethal) levels of oxidative stress in cancer cells and cancer stem cells, we use a combination of the following and administer them on an intermittent/cyclical (i.e., “pulse”) basis:

1. Disulfiram
2. Copper
3. Docosahexaenoic acid
4. Ozonated oil

The trio of disulfiram (DSF), copper (Cu), and docosahexaenoic acid (DHA; a type of omega-3 fatty acid), amplifies reactive oxygen species (ROS) in cancer cells and cancer stem cells (CSCs), ultimately leading to their demise.

Originally employed to curb alcohol addiction, DSF has shown surprising anticancer properties. One key weapon in its arsenal is targeting aldehyde dehydrogenase (ALDH), an enzyme crucial for cancer cells to detoxify ROS. By blocking ALDH, DSF disrupts this defense mechanism, leaving cancer cells vulnerable to oxidative stress.

Cu is an essential element that plays a surprising role in this anti-cancer alliance. Disulfiram has a strong affinity for copper, forming a DSF-Cu complex that readily enters cancer cells and cancer stem cells. Once inside, the complex triggers the Fenton reaction, generating highly reactive hydroxyl radicals (OH•), potent ROS molecules.

DHA is an omega-3 fatty acid found in algae oil and fatty fish like salmon and tuna. DHA acid can disrupt the membranes of cancer cells, making them more permeable to the DSF-Cu complex. Additionally, DHA can directly boost ROS production through various pathways within the cell. Furthermore, DHA gives rise to metabolic by-products called resolvins. Resolvins interact with immune cells called macrophages, which are like the body’s garbage trucks. They stimulate macrophages to engulf and remove cellular debris, including dead tumor cells and other inflammatory byproducts.

DSF weakens the cancer cell’s defenses by blocking ALDH, DHA opens the gates for the DSF-Cu complex, and Cu catalyzes the generation of potent OH• radicals. This multi-pronged attack overwhelms the antioxidant defenses and sends ROS levels soaring within the cancer cells and cancer stem cells (CSCs). This surge in ROS isn’t a mere inconvenience for cancer cells and cancer stem cells; it’s a death sentence. The highly reactive OH• radicals wreak havoc on various cellular components:

1. DNA damage: ROS can directly damage DNA, leading to mutations and ultimately cell death.
2. Disrupted metabolism: High ROS levels interfere with essential metabolic processes, crippling the cancer cell’s ability to function.
3. Inhibited angiogenesis: ROS can suppress the formation of new blood vessels, starving the tumor of essential nutrients and oxygen.

The DSF-Cu combination exhibits efficacy against CSCs by:

1. Inducing ROS-mediated cell death
2. Inhibiting their stemness properties
3. Reducing their tumor-forming potential

Overall, the combination of DSF and Cu presents a promising strategy for cancer treatment due to its ability to:

1. Target both cancer cells and CSCs
2. Induce ROS-mediated cell death
3. Disrupt tumor growth and metastasis

Oral ozonated oil contains high levels of dissolved ozone compounds called ozonides that are extremely pure, highly bioavailable, and devoid of antioxidants. These ozonides have been found to increase the level of oxidative stress in cancer cells and cancer stem cells, causing irreparable damage to the cell membrane and mitochondria, the release of intracellular calcium, and activation of apoptosis. Additionally, ozone oil has been shown to:

1. Increase oxygen tissue availability, thereby counteracting angiogenesis and metastasis triggered by tumor hypoxia (oxygen deficiency).
2. Decrease cancer-promoting inflammation.
3. Foster immune destruction of cancer cells by inhibiting tumor-associated macrophages (TAMs).
4. Improve the quality of life of those receiving chemotherapy or radiation therapy.

In summary, interfering with tumor cell energy metabolism and subsequently exposing them to ROS-generating therapy holds great promise for cancer treatment. This multi-pronged approach exploits tumor vulnerabilities, enhances cell death pathways, and potentially bypasses resistance mechanisms.

Treatment cost:

The average oncologist manages between 250 and 500 patients. Dr. Thomas limits his caseload to fewer than 50. This allows him to provide highly attentive care and to dedicate time to vital research that directly benefits his patients. The use of the medications described above requires careful medical monitoring by Dr. Thomas. After an initial in-office physical examination, treatment begins. Follow-up visits are conducted via telemedicine and yearly physical exams are performed. While under his care, patients have unlimited email access to Dr. Thomas.

The cost for our services is a flat rate of $2750 per month. This is less expensive than alternative cancer treatment in Mexico or Europe. Clinics there typically charge $7,000 to $20,000 per week (click here and scroll down to FAQs and click “What are the costs of stage 4 cancer treatments at a clinic?”). Despite their high costs, many of these clinics lack a more comprehensive understanding of tumor biology, which could pose a threat if they fail to target key vulnerabilities of cancer.

Our monthly fee includes the cost of syrosingopine and ozonated oil capsules. Syrosingopine is a blood pressure medication from the late 1950s that was phased out by the manufacturer in the mid-1960s as newer medications were developed. It has not been available at any retail or compounding pharmacy since then. To make it available to our patients, we spend a considerable amount of money to have it custom-synthesized by medicinal chemists. Other costs are for the medications available at the local pharmacy (diclofenac, disulfiram, metformin, and simvastatin) and supplements available online (copper and docosahexaenoic acid). These total a little over $100 per month. Treatment is maintained until remission or disease stabilization is achieved. This usually takes 12-18 months. Afterward, we employ a simpler and less expensive protocol. For more information, click here and here.

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