Grouppe Kurosawa: Kurosawa Kocktail™: Cancer - Cancer Treatment Targets (print)

Kurosawa Kocktail™: Cancer Treatment Targets

This essay discusses different cancers and how natural medicines can be used to treat them. Although Grouppe Kurosawa (http://www.grouppekurosawa.com) is an advocate of using natural medicines and common over the counter drugs, in specific combinations, to treat serious acute and chronic illness, we are NOT against chemotherapy or radiation. We simply believe, and correctly so, that they can be made more effective if they are combined with certain common products like ibuprofen, caffeine (and theophylline), quercetin, etc. which enhance the effectiveness of the chemo and radiation, primarily by delaying or completely inhibiting the ability of cancer cells to become resistant to the treatment. We will discuss these issues in another Kurosawa kocktail ™ document.

For the sake of simplicity, we are going to categorize cancers as lymphoid (lymphoma, and leukemia), non-lymphoid cancers (all the others except brain) and brain. In the case of the lymphoid cancers, the treatment objective is to induce apoptosis or programmed cell death in the cancer cells. This is a fairly mild method of cell death that doesn’t involve an inflammatory response. For non-lymphoid cancers, except brain, the induction of necrosis, not apoptosis, is the primary treatment objective. Brain cancers are a third category of cancers that are difficult to treat because of their location in a highly sensitive, and exclusive area of the body. These cancers can only be destroyed by apoptosis-inducing compounds that are capable of crossing the blood brain barrier

The induction of programmed cell death is a normal biochemical pathway that is activated when biochemical sensors detect something “amiss” in the metabolism of a growing cell. Programmed cell death can be activated by many different events, the most common of which are DNA damage and hypoxia, reduced oxygen availability to the cells.

The cell cycle is extraordinarily complicated and proceeds in distinct phases, such as G1, S, G2, and M. For example, in order for a cell to proceed from the G1 phase into the S phase, the period when DNA synthesis occurs, a host of biochemical events have to occur beforehand. If a problem occurs in G1 that cannot be repaired, the cell cuts its losses and commits suicide, or programmed cell death (PCD). PCD is a critical process that prevents mutations from accumulating, resulting ultimately in the development of cancer. Obviously, cancer cells, virtually by definition, have managed to survive largely by mutations in one or more PCD pathways.

Cancer cells are very unstable and grow at often unpredictable rates. Cancer cell growth is largely dictated by a constant interplay between cell death due to PCD and necrosis and cell growth. Although many early cancer cells grow in an orderly, linear fashion, advanced cells, especially those forming large tumor masses, are very heterogeneous in their genetic makeup. Some cells over express various growth hormone receptors while others do not. The blockage of these receptors by hormones, anti-hormones, drugs and monoclonal antibodies can shrink a tumor, but they cannot, alone, destroy it. Cancer cells in the same tumor mass are simply too different for any one treatment protocol to be completely effective.

The easiest way to kill a tumor mass, including a large tumor mass, is to massively induce necrosis, not PCD, in the cells. During PCD, cells shrink and break up into small blebs that are rapidly removed in a non-inflammatory manner by macrophages, large white blood cells that clear debris from the body. In necrosis, cells swell and literally explode, triggering an inflammatory reaction. It is impossible to destroy a tumor mass and to activate the process of tissue healing without inducing a vigorous inflammatory reaction against the tumor. PCD, under optimal conditions, occurs in normal tissues to clear individual cells via macrophage engulfment, a process that is completely dysfunctional within a tumor mass. A normal non-inflammatory PCD method of cell death could NEVER destroy, and clear a large tumor nor could it initiate the critical process of tissue healing.

Presently, during surgery, if a tumor mass is found to invade normal tissues, the patients are often sewn up and sent home to die. Alternatively, they are given chemotherapy or radiation therapy. After all, surgery can only eliminate tumor masses that can be seen with the naked eye. We feel the medical profession is missing an opportunity. In the future, we recommend the removal of the cancer tissue that is visually evident and the use of a Kurosawa kocktail as a backup to destroy the smaller tumor masses. The different Kurosawa kocktails for cancer can be custom modified for virtually any cancer or any medical situation.

In this protocol, we will show that direct contact of a metastatic tumor mass and a Kurosawa kocktail can induce massive and virtually immediate necrosis in the cancer cells. Although this seems like an ideal treatment protocol, it has its risks. Inducing necrosis on a large scale in an internal tumor mass could cause kidney failure. The kidneys would be unable to cope with all the debris from the liquefying tumor mass. In the spectacular case of Anna, documented in her own words in an essay on this web site (http://www.grouppekurosawa.com/anna.htm), she had a massive stage four breast cancer mass on her chest (10 x 10cm and 3cm deep) that she topical treated. Almost immediately, Anna was able to wipe her dead tumor tissue off her chest every morning in the shower. This wouldn’t be possible if the bulk of the tumor mass was in the liver. This is why we recommend surgery as a first step when large tumor masses are involved. The kocktail can follow up and destroy what’s left of the cancer tissues after the surgery is completed.

After years and years of investigating every conceivable biochemical pathway important in the survival and growth of cancer cells, we have elected to concentrate on the following twenty-two. Rather than choosing one pathway to treat, an approach bound to fail, we have elected to target all twenty-two at once. Considering the unpredictability of cancer cell growth, moderate treatment protocols are not an option. Hit the cancers with anything that works, making certain to avoid natural medicines that antagonize one another.

Although we are attempting to primarily induce necrosis in non-lymphoid cancers, PCD is also occurring on a large scale. Since the PCD-induced cellular blebs cannot be cleared effectively from a tumor mass, the blebs inevitably fall apart and induce a more extensive inflammatory response, our primary goal in all non-lymphoid cancer treatments (except brain).

The Twenty-two Treatment Targets of lymphoid and non-lymphoid tumors are as follows. They are not listed in order of importance. We will list more Targets as our knowledge base increases over time.

Inhibit the activity or synthesis of the glucocorticoid receptor within the cancer cells.
Inhibit the activity of the PI3K/AKT cell activation/survival- pathway.
Inhibit the activity of the RAS/MEK/ERK cell activation pathway.
Inhibit the activity or synthesis of HIF-1, hypoxia inducible factor, within the cancer cells.
Deplete NAD in the cancer cells.
Inhibit the activity or synthesis of 5-lipoxygenase within the cancer cells.
Inhibit the activity of the proteasome complex.
Inhibit the activity or synthesis of fatty acid synthase.
Increase the leakage of cytochrome C and SMAC/DIABLO from the mitochondria.
Decrease the synthesis of peroxynitrite.
Increase the synthesis of TRAIL.
Decrease the activity or synthesis of Nuclear Factor-KappaBeta
Block egress of metastatic cells out of the bloodstream.
Block histamine synthesis in cancer cells.
Block the activity or synthesis of Cox-2.
Inhibit telomerase enzyme induction.
Decrease the activity or synthesis of ETS transcription proteins.
Increase the synthesis of EGR1 transcription proteins.
Increase the synthesis of ceramide in cancer cells.
Decrease the activity or synthesis of the enzyme CK2 (casein kinase 2).
Decrease tyrosine kinase activity (inhibit HER2, EGF and VEGF growth related hormones.
Inhibit the activity of NADH oxidase over expressed on the membranes of cancer cells.

YUCKKO™ AND QUERCUR™ TREATMENT PROTOCOLS

There is no perfect treatment protocol for any disease, least of all cancer. Some cancer respond very well to gentle treatment protocols that emphasize death by programmed cell death, while other, more virulent, aggressive forms of cancer can only be killed by necrosis. Radiation and chemotherapy kill primarily by inducing massive necrosis in tumor masses, which makes them, to date, the most effective forms of cancer treatment. Unfortunately, chemotherapy and radiation are non-selective killers. They kill ALL routinely growing cells, such as those in the bone marrow, skin, gastrointestinal tract, hair follicle, and the cells attempting to repopulate tissue wounds.

The natural medicines in YUCKKO™ and QUERCUR™ have no or very low toxicity towards normal cells, yet, under certain circumstances, they interfere significantly with the growth pathways of cancer cells, resulting in their death by programmed cell death or necrosis. When some of these natural medicines are additionally combined with commonly available supplements, they become extremely powerful treatment modalities. The secret, which we are now publicly disclosing to the world, is how we get these substances into the body in sufficient concentrations to have a therapeutic effect.

Coconut milk!!!

We know…sounds stupid, simplistic and ridiculous. Coconut milk is the “magic” delivery vehicle for introduction of these extremely powerful natural medicines into the body? In a word, YES! Coconut milk is a combination of coconut water and coconut, homogenized into a milk of sorts. It is 50% saturated fat, but the saturated fat contains a very high concentration of lauric acid, a medium chain fatty acid that is a wonderful food and an enhancer of programmed cell death in cancer cells. Coconuts are the only dietary source of lauric acid; it doesn’t exist in other foods to any meaningful extent. Coconut oil was used by theatres in the US to flavor popcorn until the US cereal grain industry lobbied to have this “dangerous” saturated fat replaced with cereal grain oils. Coconut oil is very healthy, because the lauric acid, a 12 carbon fatty acid, is too short to be incorporated into arteries. In fact, the reverse is true. Lauric acid is a wonderful source of energy, as are all fatty acids, at least in comparison to sugars and proteins, and is an anti-cancer natural molecule as well. So you decide…politics and corporate greed or scientific reality. It shouldn’t be a difficult decision.

Many natural medicines, such as quercetin and curcumin, exist in two basic biochemical forms. One form, called a glycoside, has a sugar attached to it. This molecular modification makes the compound soluble in water and theoretically bioavailable. Unfortunately, glycosides have little biological activity. The non-glycoside versions of natural molecules like quercetin and curcumin have full biological activity but poor solubility in water. They are, in fact, lipophilic or lipid (fat) loving. So we dissolved them in a fat, coconut milk, and introduced them into the body via the lymphatic system, which is how fats enter the body.

Orally ingested molecules enter the body in two ways. Peptides, sugars, and other molecules, such as natural medicines (flavonoids, flavones, etc.) enter the body via the portal system. This is the classic method of entry into the body via the blood. Entry into the blood via the intestines is a complicated process. First, the molecules have to be actually absorbed by the cells in the intestines. If they enter the intestinal cells, they can be immediately modified by the cells and released back into the lumen of the intestines in a “swinging door” fashion and excreted. Assuming a molecule like quercetin makes it past this first step, it can be further modified or destroyed by the liver. This is called the first pass phenomenon and it’s the “pox on the butt” of the entire pharmaceutical and biotech industry. The liver is a wonderful organ that protects us against strange foreign molecules, including therapeutically beneficial molecules like modern drugs and natural medicines, such as quercetin and curcumin. Sometimes, the liver, in its “ignorance”, works against us.

There is a way around this problem, which the pharmaceutical industry has been busy trying to exploit for years. Fats, as in oils of any kind, do not enter the blood from the intestines. They directly enter the lymphatic system, the system of ducts that bathes all the tissues of the body. The lymph fluid originates from the blood but it is a completely different circulatory system in the body. The clear liquid that moves from the blood to the tissues bathes all the tissues in the body with nutrients, drugs, and oxygen. It also removes waste products. This liquid is collected in lymphatic ducts and returned to the blood where waste products are removed by the liver and kidneys. If you can target the lymphatic system with a drug or natural medicine, thereby bypassing initial contact with the blood circulatory system, you can substantially enhance the introduction of biologically active substances into the body.

Introducing medicines directly into the lymphatic system is especially important if you are attempting to treat an immunological disease, such as lymphoma, or a viral disease such as HIV. These diseases exist, so to speak, in the lymphatic system. But this same argument applies to carcinoma and sarcoma cancers as well. Growth factors for endothelial cells (blood vessels) such as VEGF (vascular endothelial growth factor) are secreted from established tumors under a variety of conditions, including reduced oxygen tension. VEGF not only stimulates the growth of new blood vessels into tumors, it also stimulates established blood vessels to “leak”, as in to release enhanced amounts of lymphatic fluid, protein, nutrients, and oxygen from the blood into the tissue spaces. Contrary to current medical dogma and scientific models, the requirement for blood vessel growth into tumors depends largely on the geometry of the tumor mass. Tumors with a large surface area, like Anna’s open chest tumor, “wept” massive amounts of lymph fluid, but didn’t bleed. There were no or few blood vessels feeding the cancer growth. The growth of the tumors and the spread of metastatic cells were promoted by lymph fluid and its vascular system. Therefore, introducing medicines directly into the lymphatic system is an attractive alternative to IV injections or blood targeted oral formulations.

GLUCOCORTICOIDS AND CANCER

Glucocorticoids do not cause cancer, but they can protect cancer cells from dying of suicide or programmed cell death, thereby perpetuating their existence and spread throughout the body. Although glucocorticoids, such as prednisone and dexamethasone, are frequently used in the treatment of lymphomas and leukemias, they should never be used to treat non-lymphoid cancers. Presently, dexamethasone is used in conjunction with chemotherapy to prevent chemo-induced nausea, edema and other problems. Unfortunately, the use of glucocorticoids like dexamethasone in the treatment of non-lymphoid cancers, for whatever reason, is seriously counterproductive.

During a stress response, glucocorticoids induce programmed cell death in unnecessary or extraneous lymphoid cells. Immune cells that have been activated by antigen and immune hormones are resistant to the apoptosis inducing effects of elevated glucocorticoid concentrations. However, and this is a point largely forgotten or ignored by many in the medical profession, glucocorticoids stabilize virtually all other cells in the body against damage during an acute stress response. Glucocorticoids accomplish this by inhibiting the ability of cells, whether they are brain, liver, kidney, skin, breast, prostate, or whatever, from committing suicide via programmed cell death in the face of an equilibrium disruptive event, such as a temporary lack of oxygen. The ability of glucocorticoids to stabilize the cells of the body is absolutely critical to survival and the maintenance of homeostasis.

The ability of glucocorticoids to stabilize the cells of the body during normal stress has certain drawbacks when cancer is involved. One of the first biochemical events that occur during a cells progression to becoming fully malignant is an increase in the number of glucocorticoid receptors within the cell. In addition to an increased number of hormone receptors, glucocorticoid receptors can be activated inappropriately by a process called nitration. The nitration of proteins occurs when a particular amino acid, such as tyrosine, is covalently modified by a nitrate group. In most cases, this form of modification inhibits the activity of the protein. Glucocorticoid receptors are actually activated by this process. The major donor of nitrate groups is a highly chemically reactive molecule called peroxynitrite. Peroxynitrite is involved in many diseases processes and is almost always associated with inflammation.

In addition to genetic changes to the glucocorticoid receptor and chemical modifications to the receptor, psychological stress, characterized by an increase in the level of glucocorticoids and epinephrine in the blood, also contributes to the growth and spread of cancer cells throughout the body. It is well established that the five year survival rate after successful cancer therapy is heavily influenced by the psychological status of the patient. Patients who experience severe anxiety or feelings of helplessness have a greater incidence of cancer reoccurrence. In a very real sense, the fear of cancer reoccurrence is a participating factor in the actual rate of reoccurrence.

In addition to inhibiting programmed cell death in cancer cells, glucocorticoids are well established anti-inflammatory agents. Although most, if not all cancers begin at sites of chronic inflammation, the inflammation associated with cancer is chronic, and weak, rather than acute and strong. The presence of a weak inflammatory environment may be due to excessive binding of glucocorticoids within the tumor mass. Stress, resulting in an increase in glucocorticoid synthesis and release, is also a factor in protecting cancer cells from PCD.

A good example of the difference between chronic and acute inflammation is the analogy of bacteria growing in nutrient rich warm water. As long as the temperature is not too high, the bacteria will grow rapidly. However, if the temperature is increased, the bacteria rapidly die. This is very similar to what happens in a cancer lesion. The inflammatory hormones are growth promoting in low concentrations, but deadly when elevated beyond a certain concentration. In a very real sense, it you want to kill cancer cells, especially those associated with a tumor mass, you MUST induce an acute, deadly inflammatory response against the tumor. No other treatment protocol will work. This is exactly what occurs when tumors are treated with chemotherapy and radiation. Radiation and chemotherapy drugs induce a massive inflammatory response within the tumor mass, resulting in their death from both PCD and necrosis, primarily the latter. Although a radiation beam can be targeted, chemotherapeutic drugs cannot. They will kill any growing cells, normal or carcinogenic, hence the death of hair follicles, bone marrow failure, damage to the gastrointestinal tract resulting in vomiting, and skin lesions. Chemotherapy drugs also cause what some people called “brain freeze”, a state of confusion that takes a long time to go away. In stark contrast to radiation and chemotherapy, the natural medicines in the Kurosawa kocktail protocols kill only cancer cells with very discomfort to the patient.

After an acute inflammatory response is induced against the tumor, resulting in necrosis and increased inflammation, the inflammation should be allowed to “ride” so the lesion heals properly by the migration of new tissues into the wound. There are two fundamental phases of inflammation at work here. The first is destruction of the cancer cells and the second, equally important, is the healing of the wound. Both phases of inflammation are dependent on the systematic release of pro-inflammatory immune hormones, hormones whose synthesis and/or release is inhibited by glucocorticoids.

Another factor worthy of mention is the immune response against cancer cells. Although some scientists have attempted to activate the immune response against tumor masses, these attempts have always failed. Cancer cells secrete a number of factors, such as prostaglandins, histamine and reactive molecules like peroxynitrite that inhibit the ability of white blood cells to recognize and destroy cancer cells. Immunotherapy is an interesting concept, but it fails to recognize the harsh conditions under which most advanced cancers survive in. Cancer cells have adapted to these conditions but normal white blood cells have not. Even if a T lymphocyte could recognize a particular cancer cell, the factors secreted by the cancer cells would prevent the activation of the T lymphocyte and subsequent death of the cancer.

In summary, glucocorticoids affect non-lymphoid tumors in four fundamental ways. First and foremost, they protect, as in prevent, cancer cells from dying of programmed cell death. Second, they inhibit the biochemical pathways necessary for mounting an acute, destructive inflammatory response against the tumor mass. Third, they inhibit the biochemical pathways involved in new cell migration into the lesion and the secretion of collagen, the polymer or scaffold upon which most cells rest. Fourth, they inhibit the activities of both specific (activated T lymphocytes) and non-specific (natural killer cells and macrophages) immune responses against the cancer cells.

In the Grouppe Kurosawa model of cancer treatment, it is necessary to partially block the synthesis of hydrocortisone in the adrenal glands, and to curtail hydrocortisone binding to cancer cells. This will release cancer cells from the protective shield provided by enhanced hydrocortisone binding. This is step one in our treatment protocol and it can be accomplished with the simple, inexpensive natural sleep hormone melatonin. We like to call this step “releasing the parking brake”. Melatonin is one of God’s most remarkable natural drugs. More about melatonin later.

THE PI3K/AKT BIOCHEMICAL PATHWAY

The PI3K (phosphatidylinositol 3-kinase)/ AKT (protein kinase B) biochemical pathway is fundamental to the survival of cells after activation by growth factors (epidermal growth factor, platelet derived growth factor, insulin, insulin-like growth factor, vascular endothelial growth factor, HER growth factors, etc) and cytokines (immune hormones such as interleukin-3 and interleukin-6, etc.). If activation of the PI3K/AKT (henceforth PIA) pathway is blocked, the cellular activation signal initiated by a growth factor or cytokine will result in the death of the cell by PCD.

As we previously discussed, cell growth is a precarious process. The fragile nature of cell growth was built into “the nature” of a cell as a fail-safe mechanism. When a growth factor/cytokine stimulates biochemical pathways that activate a cell to divide, they also activate the PIA pathway to protect the cells from self-destruction along the way. The PIA pathway accomplishes this critical task in numerous different ways.

First, an abbreviated overview of the complicated PIA pathway is in order.

When a growth factor/cytokine (henceforth GFC) stimulates its receptor on the outer membrane of a cell, it causes the receptor to undergo a conformational change. This conformational change allows the receptor protein to bind the PIA enzyme and localize it to the inner membrane of the cell. PIA is an enzyme that phosphorylates, or adds a phosphate group to the lipid phosphatidylinositol. These newly phosphorylated lipids draw other molecules to the inner surface of the membrane, thereby setting off a chain reaction of biochemical activity. The phosphorylation reaction mediated by PIA can be reversed by a molecule called PTEN, a phosphatase that removes the phosphate associated with the 3 position on the phosphatidylinositol molecule. If the PTEN molecule is inactive, as it is in the majority of cancers, the PIA biochemical pathway can proceed largely unabated by feedback inhibition.

One of the molecules that bind PIP3, the phosphorylated phosphatidylinositol lipid, is PDK1, a kinase. This enzyme adds a phosphate group to the AKT enzyme, among others, thereby activating it. AKT (protein kinase B), in turn, activates and deactivates a host of other proteins involved in cell proliferation and cell survival. PDK1 is a very important enzyme because it activates numerous other protein kinases from the AGC group (PKA, PKG and PKC).

PTEN is considered a tumor suppressor gene, because the introduction of an active PTEN gene into almost any cancer will cause it to stop growing and die. Although PTEN can inhibit other biochemical pathways, such as RAS/RAF/MEK/ERK and FAK, the pathway involved in cytoskeletal rearrangement, its inhibition of the biochemical pathways “downstream” of PI3K activation are of paramount importance.

In the laboratory, we can inhibit the activation of specific biochemical pathways with pin point precision. This isn’t possible in the real world of the body. Fortunately, nature has smiled on us and provided us with natural, non-toxic inhibitors of the PI3K pathway. Although these natural inhibitors kill tumor cells, they do not kill normal cells, quite unlike radiation and chemotherapy.

HIF-1 AND CANCER

All oxygen dependent organisms, from bacteria to humans, must be able to sequester oxygen in their environment in order to live. Hypoxia refers to a reduction in the supply of adequate amounts of oxygen, resulting in a failure to generate enough ATP to survive. Hypoxia can occur for many reasons. Climbing a tall mountain can cause hypoxia and so-called oxygen sickness. Disease states such as arteriosclerosis restrict blood flow hereby depriving cells of oxygen, and predisposing people to heart attacks. Massive bleeding, whether due to an operation or injury, can also cause hypoxia. Hypoxia is a stress-inducing situation which, under certain circumstances, can induce programmed cell death (PCD) in cells. Obviously, it would not be in our survival interests to have a large number of our cells die, and our organs fail, if they were temporarily deprived of oxygen. This is where the protein HIF-1, hypoxia-inducible factor 1, plays an important role in maintaining the homeostatic balance of the body.

HIF-1 is induced by a reduction in the level of oxygen experienced by the body. When expressed, HIF-1 blocks PCD, and regulates the activity of literally hundreds of enzymes and proteins in the body in an effort to cope with the reduced oxygen tension. While some enzymes and proteins are turned on, others are turned off. Genes that regulate the uptake and metabolism of glucose are powerfully activated by HIF-1. This makes perfect sense since enhanced glucose uptake and its metabolism via glycolysis is the fastest way to generate ATP and to correct the metabolic imbalance caused by a reduction in available oxygen. Although the metabolism of sugars, fats and proteins via respiration requires oxygen, the rapid metabolism of glucose via glycolysis does not. The rapid metabolism of glucose in the presence of oxygen is called aerobic glycolysis and it is a fundamental characteristic of the metabolism of cancer cells.

Note: We aren’t remotely done with this essay, a long one. We simply have too many essays to write and not enough time in the day to write them. We’re trying our best so please be patient.