Insulin Potentiated, Low-dose chemotherapy (IPTLD): a cancer advantage turned disadvantage
Why is insulin so important in cancer? Why are insulin receptors so important in cancer? And why is insulin signaling important? They are a part of the cancer environment set up and at the core of the altered cancer metabolism in the tumor microenvironment. In cancer, many conditions come together that all feed each other: hyperglycemia, hyperinsulinemia, increased NF-kappaB = inflammation, increased IL-6 signaling = inflammation and cytokine burst, insulin resistance, increased IGF-1 signaling, increased insulin receptor expression, increased PI3k/Akt/mTOR = growth, increased TLR-4, increased gluconeogenesis, and many others. All drive dysfunction when it comes to a pro-cancer environment and metabolism. Normal metabolism need not apply when it comes to cancer.
The whole body is not a tumor microenvironment. Non-cancer environments do co-exist with the tumor micro-environments within the same individual with cancer. In cancer, normal metabolism and cancer metabolism co-exist. In people with cancer, therapeutic approaches that seek to work within normal metabolism will not necessarily affect the cancer microenvironment’s altered metabolism. This thinking is how high-dose IV vitamin C can be pro-oxidative and anti-oxidative at the same time. The environment dictates the response. Likewise, insulin can promote normal cell metabolism in healthy cell environments and feed cancer’s ravenous appetite for growth in tumor micro-environments at the same time. The complexity of insulin dysregulation in cancer metabolism in the tumor microenvironment is at the heart of how insulin’s addition to low-dose, metronomic chemotherapy works. We call this low-dose, insulin potentiated chemotherapy (IPTLD). This statement is a mouth full, for sure, but it summarizes the treatment strategy well. Low-dose chemotherapy’s potentiation with insulin takes a perceived cancer advantage, hyperinsulinemia, insulin resistance, increased insulin receptors and turns it into a cancer disadvantage. The result is a targeted cancer therapy that drives a stake at the core of the altered cancer metabolism yet does not affect normal metabolism.
I want to take this discussion of insulin signaling and cancer a step deeper. I want to connect some of the many causes of cancer discussed in a previous series on holistic causes of cancer, elevated insulin levels, insulin receptors, or insulin signaling. Just a brief review, they include:
- Metabolic dysfunction
- Acid/Base balance
- Tumor Microenvironment (TME)
- Immune dysfunction
- Toxicants and detoxification dysfunction
- The Gut
- other associated deficiencies
Though these points do not involve all causes I previously discussed, specific points of interest deserve mentioning.
Why is this connection important? In addition to the benefits highlighted in the previous post, it is important to remember that the increase in insulin receptors and insulin signaling allows targeting the tumor with IPTLD to turn a perceived advantage for cancer to a disadvantage and an advantage in treatment targeting. It is all how you look at the problem. So, how does this happen?
Hypoxia is a critical driver in the genesis, growth, and spread of cancer. It is one of the key causes of cancer. Call it one of the required ‘hits’ to the system in the multiple hit theory of cancer. It is essential to realize that the hypoxia I am writing about here is not body-wide. Instead, this hypoxia is localized within the tumor microenvironment or tumor micro-environments. The number of tumor microenvironments is equal to the number of tumors. Tumor microenvironments are often just thought of in terms of one primary tumor. They can, however, be present in multiple sites all over the body simultaneously. Each new metastasis site becomes a new primary.
What is the relevance to insulin, insulin receptors, and insulin signaling? I am glad you asked.
Hypoxia induces Hypoxia Inducible Factor-1alpha (HIF-1alpha), a requirement for an insulin-mediated increase in Vascular Endothelial Growth Factor responsible for angiogenesis .
- Hypoxia Inducible Factor-1alpha (HIF-1alpha), induced by hypoxia, is required for an insulin-mediated increase in Hexokinase II 2, a glycolytic enzyme, key in tumor initiation, growth, and metastasis  .
- Hypoxia in cancer increases Insulin Receptor Substrate protein 2 (IRS-2) facilitating internal membrane insulin signal transmission to promote increased tumor cell survival, invasion, and increase in tumor cell glycolytic activity .
- Akt is a component of the PI3k/Akt/mTOR pathway’s potent pro-growth pathway, one of the more aberrantly up-regulated cancer pathways. An increase in Akt signaling increases insulin receptor production, insulin receptor expression on the cell surface. The result is an increase in insulin signaling potential 4.
The end result is that hypoxia induces an increase in insulin receptor expression via a HIF-1alpha—> IRS-2 —> Akt signaling pathway —> insulin receptor pathway. Couple the increase in insulin delivery through an increase in angiogenesis blood vessel growth and the increase in insulin receptors and IRS-2, and the table is set for growth.
You will often hear me say that inflammation is the bed that cancer lays in. This statement is without question true. But, it is essential to understand that inflammation itself is not the enemy. It is the chronic, unregulated, and dysfunctional inflammation that is the problem. Remember, cancer co-opts and adulterates normal biochemical processes for its benefit and survival, at the detriment of the rest of the body. The immune system and hormones are perfect examples of this, and I have written and discussed both previously, so I encourage you to check them out.
- Inflammation increases insulin resistance. Research points to insulin resistance as one of the major, if not the major, cause of elevated insulin levels (also known as hyperinsulinemia) and insulin signaling  . In fact, hyperinsulinemia triggers inflammation, a cancer closed-loop, and self-feeding set up by cancer.
- Obesity is associated with an increase in NK-kappaB activation and inflammatory signaling in type II diabetes. As a result, there is a direct increase in insulin resistance, insulin levels, and insulin signaling . All three are associated with cancer.
- Chronic inflammation connects insulin resistance and hyperinsulinemia with cancer .
The connection that we are looking for is with cancer. How does dysbiosis in the gut lead to systemic inflammation in a way that favors cancer?
- Gut dysbiosis has been shown to contribute to local and systemic cancer .
- The imbalance of the gut microbiome, called dysbiosis, has been shown to cause insulin resistance and hyperinsulinemia    .
- Gut dysbiosis causes an increase in gut permeability, called “leaky gut”, which increases systemic Lipopolysaccharide (LPS) circulation, which contributes to cancer  .
- Lipopolysaccharide (LPS), a gram-negative bacteria surface antigen from the gut, activates systemic Toll-like-4 receptors (TLR-4), which causes insulin resistance  .
- Lipopolysaccharide (LPS) activates Toll-like-4 receptors (TLR-4) to increase cancer invasion, growth, and metastasis  . Just an aside, for all you nerds like me, it does this through the activation of the PI3k/Akt and MyD88 intracellular pathways and NK-kappaB inflammatory signaling. It is not enough to show the end result, but the process as well.
- Certain pathogenic gut bacteria, Helicobacter pylori, have been shown to cause cancer .
- Chronic Helicobacter pylori infection causes insulin resistance . Remember, insulin resistance causes hyperinsulinemia.
This review has been a lot of deep wading through the weeds of biochemistry but is necessary. The dissenters to natural or alternative medicine often claim there is no science. The reality is, they are merely ignorant of the enormous amount of supporting science that exists. It is essential to remember that hyperinsulinemia and insulin resistance are intimately connected and intertwined. One cannot exist without the other. Insulin resistance causes hyperinsulinemia; in the converse, hyperinsulinemia causes insulin resistance . But, what is the connection to insulin receptors? What is the connection to the 6-17% increase in insulin receptor expression? What is the link to the 1,000 fold increase in insulin: insulin receptor affinity? Insulin resistance and hyperinsulinemia increase intracellular Akt activation. The end result is an increase in insulin receptors. Again, another cancer closed-loop, self-feeding cycle. See how cancer works? Cancer uses what is around, manipulates, and adulterates it, all at the expense of the host. Unfortunately, we are the hosts here.
It is one thing to have studies that point to how insulin receptor expression is increased in cancer but does this pattern exist elsewhere in body physiology? The reproduction of this type of pathway provides additional supportive evidence. Yes, and we don’t have to travel outside the world of cancer to find it. Androgen receptor (AR) resistance plays a significant role in castrate-resistant prostate cancer (CRPC). Think of CRPC as prostate cancer that is resistant to all hormonal treatments. The androgen receptor, another normal body process, is dysfunctional and is one of the problems at the heart of prostate cancer. The target receptor in the hormonal treatment of prostate cancer is the androgen receptor. Whether this is through blocking testosterone and other androgens from interacting with the AR, blocking the pituitary or hypothalamus stimulation of testosterone, or the down-regulation of AR, the androgen receptors are front and center in the hormonal attempt to block the testosterone signaling in prostate cancer. In castrate-resistant prostate cancer, androgen receptor expression is increased to overcome androgen receptor resistance   . The authors of the study, Amplification and Overexpression of Androgen Receptor Gene in Hormone-Refractory Prostate Cancer, highlight the connection:
“It has been suggested that amplification of the AR gene could cause overexpression, allowing the cancer cells to continue androgen-dependent growth even in very low levels of androgens left in serum after castration”.
Many would point to the negative feedback inhibition of insulin receptors as a result of hyperinsulinemia. That would be correct in normal physiologic negative feedback. But, in cancer, we are not talking about normal physiology, are we? Cancer hijacks normal physiology and biochemistry and corrupts it. The normal function includes the expression of many counterregulatory mechanisms, including the tumor suppressor genes p53 and PTEN to counter abnormal growth. Cancer turns this off. Normal function turns off inflammation when the healing is complete, but cancer chronically activates inflammatory signaling, i.e., NF-kappaB, IL-6, TGF-beta. The same dysfunction applies to cancer and insulin. The negative feedback of elevated insulin receptors and insulin signaling is lost so that chronic growth stimulus required for cancer survival can be supported.
In closing, the intertwined connections, the closed-loop, self-feeding cycles, and the evidence are everywhere.
Increased insulin receptors <— Activated PI3k/Akt/mTOR <— Hyperinsulinemia <—> Inflammation <—> insulin resistance—> attempt to overcome insulin resistance—> hyperinsulinemia—> increased PI3k/Akt/mTOR—> increased insulin receptors—> increased GLUT1 and GLUT3 —> increase glucose intake —> feeds the Warburg effect (aerobic glycolysis) —> metabolic demand of cancer met —> cancer growth.
One must simply look and read to learn.
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Dr. Nathan Goodyear is dedicated to disease prevention, disease resolution, and the Wellness Lifestyle through a solution-based, Integrative Medicine approach founded in science. Dr. Goodyear received his Bachelor of Arts from Louisiana Tech University and his Doctor of Medicine from LSU Health Sciences Center.
He is Board Certified in Obstetrics and Gynecology and served as the Chief Resident in Obstetrics and Gynecology at the University of Tennessee. Dr. Goodyear has practiced Integrative Medicine since 2006. Dr. Goodyear is a Fellow in Functional and Regenerative Medicine and served on the board of the American Functional Medicine Association. Dr Goodyear is licensed by the Arizona Homeopathic and Integrative Medical Board in the State of Arizona. Dr. Goodyear is a published author, Man Boob Nation–an Integrative medicine approach to low Testosterone published in 2014, and Total Testosterone Transformation published in 2017