Curcumin

Story at a glance

Curcumin is an extensively studied plant compound with impressive activity against chronically fermenting cells (CFCs or cancer). Key mechanisms of curcumin’s action include:

Curcumin is a polyphenolic compound extracted from turmeric root (Curcuma longa) which has a long history of use both as a spice and in traditional Ayurvedic medicine. Over the past two decades research has shown that turmeric’s activity is due to curcumin (diferuloylmethane), one of its components. This compound functions in the human body by regulating multiple transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that are all linked to inflammation, the underlying adaptive physiology (“pathology”) of chronic, degenerative processes (“diseases”) such as diabetes, heart “disease”, arthritis, depression, and chronically fermenting cells (CFCs or cancer).

Furthermore, at least 2000 publications in the National Institutes of Health PubMed database (www.ncbi.nlm.nih.gov/sites/entrez) have shown that curcumin has not only anti-inflammatory properties, but also antioxidant, antibacterial, antifungal, antiviral, antiproliferative (prevents CFC growth) and pro-apoptotic (stimulates CFCs to self-destruct) effects. In clinical trials curcumin has been shown to enhance survival rates among individuals undergoing chemotherapy, without any adverse effects.

Consistently, research confirms the efficacy of curcumin’s ability to eliminate CFCs without harming healthy cells, which makes it a safe, non-toxic targeted therapy. Unlike conventional treatments such as chemotherapy and radiation therapy, which indiscriminately affect all rapidly dividing cells in the body, curcumin selectively targets the distinct biology of CFCs eliminating them while sparing healthy cells.

However, when ingested orally curcumin’s efficacy is limited due to its poor absorption, rapid metabolism, and relatively quick elimination. For these reasons, intravenous administration is required to achieve therapeutic blood levels required to reduce or eradicate the tumor burden while minimizing adverse effects. To further enhance efficacy, curcumin can be combined with other metabolic therapies, each of which challenges the CFCs from a different metabolic weakness to overcome their adaptability. These metabolic therapies can be given on the same days as well as alternate days in order to exhaust the CFCs by continually putting them in a position where they require specific enzymes that they do not have in order to survive.

Curcumin tends to accumulate preferentially within CFCs thereby modulating tumor growth by modifying different cytokines, growth factors, gene expression and immune responses. Beyond its impact on CFCs, curcumin also exerts diverse physiological effects that enhance the body’s natural defense systems and overall vitality.

Key mechanisms include:

Inducing cell death

The immortal character of CFCs is a result of reprogramming of certain genes to decrease programmed cell death (apoptosis), which is how cells normally respond to stressors. Signals in the tumor microenvironment (TME) such as growth factors, inflammatory cytokines, and hypoxia (oxygen deprivation) are known to stimulate the genetic changes that promote uncontrolled expansion (replication) of CFCs. The major tumor suppressor genes, responsible for apoptosis, P53 and PTEN, are commonly inactivated in CFCs.

Additionally, a key regulator of cell replication called mTOR (mammalian target of rapamycin) is often overactive in CFCs thereby promoting rapid growth. Curcumin can reverse the activity of that and all of these regulators of cellular lifecycle back to normal, which significantly increases the death rate of CFCs. It achieves this by lowering inflammatory signals such as cytokine IL-6 and silencing hypoxia inducible factor -1α (HIF1α) which is activated under hypoxic conditions in tumors. In fact, HIF1α is fundamental to the ability of tumors to continue growing and spreading. When combined with other agents such as ascorbate (vitamin C) and quercetin (a flavonoid antioxidant produced by plants) that also silence HIF1α, CFCs are quite specifically eliminated without causing any harm to the healthy cells. Additionally, curcumin is capable of triggering apoptosis by inducing oxidative stress in CFCs. This is due to their poor antioxidative capacity, hence not being able to protect themselves, CFCs are selectively killed by this mechanism, as well.

Preventing metastases

Curcumin can prevent the spread and invasion of CFCs to distant organs through various mechanisms. The metastatic tendency of tumors is strongly linked to the hypoxic (oxygen deprived) conditions in the TME. The rapid proliferation of CFCs coupled with insufficient blood supply creates hypoxic conditions triggering adaptive changes in metabolism and behavior. Hypoxia-inducible factors, especially HIF-1α are essential proteins that enable CFCs to adapt to oxygen and nutrient deprivation by enhancing their ability to produce energy via fermentation and increase the formation of new blood vessels (angiogenesis). Moreover, hypoxia triggers CFCs to acquire stem cell-like characteristics through a process called epithelial-mesenchymal transition (EMT), leading to more aggressive, invasive, and treatment-resistant cell types.

By lowering proinflammatory cytokines and turning off HIF-1α mediated signaling within the TME, curcumin prevents multiple processes involved in metastasis formation. Curcumin inhibits new blood vessel growth inside tumors by suppressing the activity of vascular endothelial growth factor (VEGF).

Another target of curcumin are proteins that CFCs use for disrupting tissue structures. One such protein is E-cadherin, responsible for keeping cells connected, almost like a glue which is necessary to maintain tissue integrity. The loss of E-cadherin function is required by CFCs in order for them to detach from other cells and migrate freely. Curcumin decreases and prevents this by restoring the activity of E-cadherin, hence greatly minimizing the invasive ability of CFCs.

Additionally, curcumin inhibits the activity of enzymes called matrix metalloproteinases (MMPs), which play a role in degrading structural proteins in the space between cells or extracellular matrix (ECM). This protein degradation also triggers the release of cytokines and growth factors, which further promote inflammation, angiogenesis, and metastasis. Studies have found that high levels of MMPs in tumors are associated with aggressive, invasive, and metastatic tumor phenotype. By limiting MMP activity, curcumin slows down the breakdown of proteins in the ECM, which reduces the migration of CFCs to other tissues.

Enhancing the immune system

The immune system is essential in the elimination of CFCs, and when it is dysregulated or suppressed, the growth and progression of CFCs increases. On top of that CFCs develop mechanisms to evade immune attack. A major obstacle for the immune system is the TME which serves as a protective barrier. The acidity, hypoxia and various signaling molecules such as cytokines in the TME alter the composition and behavior of the immune cells. This environment typically leads to the dominance of immune cells such as T regulatory cells, whose job it is to block T cells from killing, and tumor-associated macrophages (TAMs), which not only lose the capability to “eat” the tumor, but they now, even support the tumor’s growth. These TAMs release cytokines such as TGF-β that inhibit the activity of immune cells that would normally destroy tumors such as cytotoxic T lymphocytes and natural killer cells (NK).

Curcumin can reverse this immune suppression within the TME. It does this by inhibiting the production of immune suppressive cytokines such as TGF-β and IL-10 while stimulating the release of anti-tumor cytokines such as IFN-γ and TNF-α. These cytokines reactivate T lymphocytes, NK cells and other immune cells within the TME thereby reenabling them to directly kill CFCs. It is the number and activity level of both activated T-cells and NK cells in the tumor that determine whether or not the tumor grows and survives.

Eliminating CFC stem cells

CFC stem cells are the only cells in a tumor that can metastasize because of their metabolic flexibility, providing them with a tremendous resilience able to withstand the effects of toxic conventional therapies. These stem cells are remarkably adaptable, making them not only unharmed by chemotherapy and radiation but they are actually increased in number thus promoting their growth and ability to spread. In fact, standard treatments have been proven to increase the population of CFC stem cells, even converting mature CFCs back into CFC stem cells. Moreover, both chemotherapy and radiotherapy create a favorable environment for the migrating CFC stem cells to settle in when they arrive at distant tissues.

Curcumin stands out among plant-derived compounds for its proven efficacy in targeting CFC stem cells by counteracting the processes leading to their formation. One crucial mechanism involves the inhibition of proinflammatory cytokines such as IL-6 and IL-8 which are essential in CFC stem cell generation. These cytokines, elevated by chemotherapy, are closely linked to treatment resistance and poor survival outcomes. Additionally, curcumin modulates the genetic reprogramming of CFC stem cells by reversing their stem cell-like features. For instance, curcumin inhibits the activity of aldehyde dehydrogenase (ALDH) a detoxification enzyme which makes the CFC stem cells resistant to damaging agents. By suppressing ALDH, curcumin disrupts the adaptability of CFC stem cells, making them susceptible to stressors such as treatments. Through this regulation of essential genes, curcumin shifts the phenotype of CFC stem cells towards that of a healthy cell.

Furthermore, curcumin contributes to the elimination of CFC stem cells by reversing immune suppression in the TME. Studies indicate that the immune activation and recruitment of natural killer cells into the tumor is one important mechanism by which curcumin can eliminate CFC stem cells.

Supporting antioxidative processes

In addition to targeting CFCs, curcumin has a variety of beneficial effects on the whole body. It enhances the activity of antioxidant enzymes such as glutathione supporting the body’s detoxification and the elimination processes of toxins and carcinogens. Moreover, the anti-inflammatory potency of curcumin is even greater than nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen. Curcumin’s ability to reduce inflammation is attributed to its inhibition of nuclear factor kappa beta (NF-κB), perhaps the most significant cellular regulator of inflammation. By reducing inflammation, curcumin can reduce or eliminate several adverse effects caused both by CFCs and conventional treatments including muscle wasting, weight loss, fatigue, and renal (kidney) toxicity.

In short, curcumin is a safe and potent therapy due to its ability to regulate inflammation and selectively target CFCs. Curcumin acts through multiple mechanisms to trigger cell death and prevent the formation of metastases while supporting immune function and antioxidative processes.

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