Holistic Cancer Treatment: Low Dose Chemo – Part 8

 

I have spent the last many posts discussing low-dose chemotherapy, not just conjecture or opinion, but the extensive body of science supporting low-dose chemotherapy. This information is readily available. Low-dose chemotherapy goes by many names: metronomic, low-dose metronomic, low-dose, ultra-low dose, fractionated. These various titles for low-dose chemotherapy originated in the late 20th and early 21st centuries. In terms of names and titles, they are the new kids on the block. They didn’t set the trend; they followed the trend. The original trendsetter was Insulin Potentiated Therapy (IPT), also known as Insulin Potentiated Low-dose Therapy (IPTLD). This chemotherapy approach was first proposed in 1933 by D. Perez Garsia, and was its first successfully treatment for cancer in 1943 [1]. Since, IPTLD has spread across the entire world. That is over 77 years of clinical use of IPTLD by physicians worldwide! This treatment sustainability over time approaches eternity in the universe of medical treatments.

It all begins with insulin. Dr. Lodi, the founder of an Oasis of Healing and Oasis International, is a living pioneer in the field of integrative cancer treatment and was one of the first U.S. physicians to bring IPTLD to the treatment of cancer in the U.S. Dr. Thomas Lodi wrote about insulin and IPT in an original article, Chemotherapy Causes Resistance and Spread of Cancer, IPT to the Rescue:

“Insulin has a myriad of consequences by triggering multiple biochemical processes in cells; however, the main purpose of insulin is to regulate energy production in the body by increasing uptake of glucose into cells and stimulating the production of fat deposition to store any excess glucose. One of the enzymes that is stimulated by insulin is called delta-9-desaturase, which basically makes the membranes or “skin” of the cells liquid and permeable rather than relatively solid and impermeable. Cancer cells are known to have from 6 to as much as 17 times more insulin receptors on their cells and these receptors have a 60% greater affinity (“stickiness”) for insulin. Increasing the insulin receptor status on their cell membranes is an essential survival mechanism undertaken by cancer cells because they metabolize sugar differently than healthy cells.”

Insulin receptors are a member of the tyrosine kinase class of membrane receptors that have oncogenic (cancer stimulating) activity. In breast cancer cells, there has been shown to be an 80% increase in insulin receptor expression compared to non-breast cancer cells [2]. The over expression of insulin receptors is not confined to breast cancer alone, but is found in colorectal, pancreatic, lung, thyroid, and ovarian cancer [3]. Think of these receptors as doorways; the more doorways available, the more potential to flood glucose into the cancer cell to drive growth. In cancer, insulin’s primary, pro-growth signaling occurs through insulin receptor signaling [4] [5]. In addition to insulin, Insulin Growth Factor-1 (IGF-1) is a potent initiator and important growth factor in an equal variety of cancer types [6] [7]. Insulin and IGF-1 receptors are very similar, what we call homologous. How much similarity? Try 70% homology or similarity [8] [9]. As a result, Insulin can bind to IGF-1 receptors and IGF-1 can bind to insulin receptors to cross pollinate if you will. In addition, insulin receptors and IGF-1 receptors can join to create a kind of super receptor that bind both insulin or IGF-1. So, we can’t just look at insulin through the limited lens of insulin receptors; we have to consider its cross pollination with IGF-1 receptors as well. This cross pollination and receptor combination significantly increases the previously stated 6-17% increase in cancer insulin receptor expression. Activation of these receptors and their downstream, internal signaling pathways activates cancer growth, survival, metastasis, and even treatment resistance [10] [11] [12]. A 2011 review article, The Insulin Receptor: a New Target for Cancer Therapy [13], summarizes the significance of insulin and IGF-1 homology in cancer:

“Although these two receptors are highly homologous and are coupled to very similar intracellular substrate networks, in normal adult tissues insulin and IGFs stimulate specific functions, such as glucose metabolism for insulin and cell growth and proliferation for IGFs. However, in particular conditions, such as cancer, this signaling specificity is partially lost and both receptors may share similar biological functions. As the shared signaling pathway has an important role in cancer development and progression…”

It is one thing to prove a positive, that fact that cancer cells over express insulin receptors and excess insulin simulates these high affinity receptors to drive growth and metastasis.  How about prove the negative effect through the elimination of insulin receptors? The down regulation of insulin receptors have been shown to decrease cancer growth, angiogenesis, lymphangiogenesis, and metastasis [14]. The positive effect is proven and the negative effect is proven. That is powerful evidence of the coordination of insulin and insulin receptors in cancer.

To prove the naysayers wrong, we must dive deeper into the science; again, the evidence is readily available to find and read. One just needs to look and read. This deeper level of evidence can be found behind the curtain of some of the internal cell signaling pathways that insulin activates in cancer?

  • PI3K/Akt/mTOR

The PI3k/Akt/mTOR internal growth signaling pathways are often up-regulated in cancer [15]. Research advocates that the PI3K/Akt/mTOR is one of the most common altered, unregulated in the case of cancer, pathways in cancer [16] [17]. Insulin stimulation of the PI3k/Akt/mTOR pathway increases proliferation up to 40% above baseline [18]. It is also interesting to note, Akt increases the production of insulin receptors. The perfect closed loop, self-regulated growth stimulation.

  • Mitogen-activated protein kinase (MAPK)

Another insulin intracellular mediated pathway, Mitogen-activated protein kinase (MAPK), is important in cancer genesis, growth, survival, and metastasis. Insulin activates the MAPK signaling pathway  [19].

  • Vascular endothelial growth factor (VEGF)

Insulin stimulates Vascular Endothelial Growth Factor (VEGF), which is vital to angiogenesis [20] [21] [22]. Angiogenesis is the tortuous, abnormal blood vessel growth characteristic of cancer, yet crucial to its survival. Angiogenesis is the lifeblood supply for cancer. Through VEGF stimulated angiogenesis, insulin stimulates and supports cancer life support.

  • NF-kappaB

Insulin stimulates NF-kappaB, which is the DNA on-switch for chronic inflammation production [23]. Inflammation is the bed in which cancer lays. Cancer needs inflammation, and cancer produces inflammation; again, another closed-loop cycle. Evidence points to inflammation as the driving force behind insulin resistance. It is insulin resistance that drives an increase in insulin levels (hyperinsulinemia). Insulin resistance is when the insulin receptors do not effectively respond to insulin. Think of a knock on the door, yet nobody answers. Contrary to common thought, it is not sugar that drives insulin resistance, but inflammation. For example, inflammation signaling via lipopolysaccharide (LPS) has been shown to trigger body-wide insulin resistance through a process called metabolic endotoxemia [24] [25]. Where does LPS in metabolic endotoxemia originate from? Lipopolysaccharide originates from dysbiosis and inflammation in the gut. Biochemically, that is a long way from insulin receptors, glucose metabolism, and cancer potential. But, it shows the limitations of the compartment thinking so prevalent in conventional medicine today.

The question is, does this have any implication in cancer? Absolutely! The specific significance is between the interaction of LPS and toll-like 4 receptors (TLR4) in the growth, immune evasion, and cancer metastasis [26] [27]. It is important to note, maximum to tolerated toxicity chemotherapy causes metastasis through the increase and stimulation of the same TLR4 [28] [29] [30] [31]. Insulin resistance drives an increase in insulin levels, called hyperinsulinemia, which increases insulin receptor production. In conclusion, inflammation—>insulin resistance—>increase in insulin and insulin receptors—>cancer growth. Via an increase in TLR4 expression, maximum to tolerated toxicity chemotherapy only accelerates this process.

  • Wnt

The Wnt pathway plays an important role in carcinogenesis, growth, metastasis, and cancer stem cell activity in a wide variety of cancer types [32]. Insulin stimulates Wnt signaling.

  • Endothelial nitric oxide synthase (eNOS)

Endothelial nitric oxide synthase is an enzyme that makes nitric oxide out of oxygen and the amino acid, arginine. In addition to eNOS, neuronal NOS, inducible NOS, and mitochondrial NOS have been identified. Insulin activates eNOS nitric oxide production, which inhibits apoptosis, promotes angiogenesis, growth, invasion, and metastasis [33]. The majority of research points to a pro-cancer effect by eNOS activation. It is the tumor environment of cancer that effects the pro-cancer versus anti-cancer affects of eNOS by insulin.

In addition, the augmentation effects by insulin are shown to occur with a wide variety of chemotherapy agents [34]. It seems like I have been writing a lot about chemotherapy lately, but I wouldn’t say I like writing about chemotherapy. One day, Dr. Lodi and I want never to have to use IPTLD. Until that time, the key to chemotherapy is to target and use the lowest chemotherapy dose possible. Fortunately, with the lower dosing of chemotherapy, there is an increase in the anti-cancer effects (angiogenesis, immune-stimulating…) and a reduction in side effects. Win, Win.

How does IPTLD work?

Previously published in Holistic Provider in the Fall of 2006 by Dr. Lodi:

“Cancer cells, unlike other cells in human beings are anaerobic. That means they can not use oxygen when they metabolize glucose (burn sugar) for energy. A healthy, oxygen burning cell can produce 38 ATPs (energy packets) from one molecule of glucose and one molecule of oxygen. A cancer cell can only produce 2 ATPs from one molecule of glucose in the absence of oxygen. Obviously then, cancer cells are very inefficient at producing energy. As a consequence, they need 19 times more sugar (glucose) than non-cancerous cells. In order for any cell to absorb sugar, insulin is required. Insulin is the ‘key’ that opens the ‘lock’ on the cell to allow sugar to pass through. The ‘locks’ on the cell surface are called insulin receptors. Cancer cells have developed a very simple but effective strategy which allows them to get more of the available sugar than their neighbors, the non-cancerous cells. They simply have many more insulin receptors than non-cancerous cells! Having many more receptors, cancer cells are able to bind and use more of the available insulin than all the other cells. So whether one eats a banana or a candy bar, the cancer is fed first and the rest of the cells get the ‘leftovers’.

This knowledge can be used to target the cancer cell with cytotoxic agents (chemotherapy). Kind of like, a ‘smart bomb’. By administering small amounts of insulin, it is possible to ‘select’ the cancer cells from amongst all the other cells in the body because they bind the insulin much more quickly. There are a multitude of effects upon cells when insulin binds to them and one of these effects is that the cells become more permeable (creating openings). Once the cancer cells have been targeted by the insulin to ‘open their doors’, small amounts of the appropriate chemotherapeutic drugs can be administered. This is usually from 5% to 10% of the standard dose. Much of what is administered becomes absorbed into the cancer cells (permeable) and not the normal cells (relatively “hard”). IPT is able, therefore, to take advantage of the powerful cytotoxic (cell-killing) effects of standard chemotherapy without having to use high doses.

Because the dosing is low, side effects are minimized and the treatments can be given more frequently giving cancer cells less time to become resistant to the drugs.”

What does the evidence say about the addition of Insulin for the potentiation of low-dose chemotherapy in cancer treatment? Quite a lot, actually. Again, one simply needs to have a desire to look and read. Intellectual laziness need not apply. Here are some highlights of the research:

  • IPTLD increases chemotherapy drug uptake [35] [36] [37] [38] 28
  • IPTLD increases cancer cell susceptibility to chemotherapy cytotoxic effects 1 32 [39] [40]
  • IPTLD increases programmed cancer cell death (apoptosis) [41] [42]
  • IPTLD significantly inhibits cancer growth and associated signaling 23
  • IPTLD maintains significantly higher lymphocyte levels [43] [44]
  • IPTLD reduces cancer cell mobility 23
  • IPTLD reduces circulating tumor cells 23

A simple summary of the research is that pretreatment with insulin in IPTLD increases cancer-killing effects (cytotoxicity) of paclitaxel, 5FU, cisplatin, and methotrexate; and significantly increases positive treatment outcomes in multidrug-resistant metastatic cancer 23. Another win, win.

I will let Dr. Lodi, the founder of An Oasis of Healing, close this post out:

“Insulin is Nature’s ‘bow’ that allows us to aim straight into the ‘target’ (cancer cells).

The conventional method of chemotherapy delivery is like throwing a hand grenade at a fly on the wall. We prefer a more rational and direct method, like using a fly swatter, although in that case, we would probably shew the fly out of the window rather than kill it.

In this regard, the Hippocratic Oath is taken very seriously.  ‘Primum non nocere’ or ‘First, do no harm’.

If the immune system is significantly harmed while attempting to destroy the cancer, it would be a great and perhaps fatal, disservice to the patient. For it is the immune system which keeps us clean, renewed and protected from infections, toxins and cancer. And there is an answer for cancer; it is called a healthy immune system!”

Well said, Dr. Lodi.

_____

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