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Curcumin hype and potential risks

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After years of supplementing with curcumin, I realized that it's completely useless against CML, but may work pro-CML since it's a potent SIRT1 and Nrf2 activator, although it's not clear at what doses.

The fact that oral administration cannot cross nano-mol concentrations in blood and it cannot be maintained for several hours was whitewashed from most papers which prove effectiveness of micro-mol concentrations.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.24967

Most of the evidence that supports the therapeutic potential of curcumin is mainly based on in vitro studies in which curcumin was tested at concentrations in the micromolar range. Several reports have demonstrated, however, that the plasma concentrations of curcumin in people taking relatively high oral doses of this compound are very low, typically in the nanomolar range (reviewed in Ref. 4). For instance, a recent study examined the pharmacokinetics of a curcumin preparation in 12 healthy human volunteers 0.25–72 hr after an oral dose of 10 or 12 g. Using a high-performance liquid chromatography assay with a limit of detection of 50 ngmL1, only 1 subject had detectable free curcumin at any of the time points assayed.5The fact that curcumin also undergoes extensive metabolism in intestine and liver6,7means that high concentrations of curcumin cannot be achieved and maintained in plasma and tissues after oral ingestion.

As far as cancer is concerned, in vitro studies have demonstrated that cancer cells do not die unless they are exposed to curcumin concentrations of 5–50 µM for severalhours.4,9,10 Because of its poor bioavailability, these concentrations are not achieved outside the gastrointestinal tract when curcumin is taken orally. Because of its extensive metabolism in intestine and liver, these concentrations cannot be maintained for several hours in the gastrointestinal tract. This suggests that the chemotherapeutic potential of oral curcumin is limited even for the treatment of cancers of the gastrointestinal tract. Accordingly, when 15 patients with advanced colorectal cancer were treated with curcumin at daily doses of 3.6 g for up to 4 months, no partial responses to treatment or decreases in tumor markers were observed.11

As discussed before, the plasma concentrations of curcumin in people taking relatively high oral doses of curcumin are very low, typically in the nanomolar range. This means that the oral administration of curcumin does not lead to cytotoxic concentrations outside the gastrointestinal tract.

https://www.ejmoams.com/ejmoams-articles/oxidative-damage-and-brain-atro...

Fifteen clinical trials focused on cancer patients receiving different dosages of curcumin have been reviewed systematically and critically to compare the effect of this antioxidant in the different groups. This minireview primarily focuses on the application of curcumin in the treatment of various forms of cancer in vivo and does not consider data from in vitro and experimental studies that are out of such focus. To establish direct evidence of a potential effect of curcumin treatment and its anti-tumor activity, further investigations should be conducted.

SIRT1 Activation by Natural Phytochemicals: An Overview
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426493/

Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis
https://www.sciencedirect.com/science/article/pii/S0006497120460501

Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib
https://pubmed.ncbi.nlm.nih.gov/22340598/

SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells
https://www.nature.com/articles/onc201283

SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia
https://ashpublications.org/blood/article/124/1/121/33146/SIRT1-prevents...

Curcumin Activates the Nrf2 Pathway and Induces Cellular Protection Against Oxidative Injury
https://pubmed.ncbi.nlm.nih.gov/31622191/

Nrf2-Related Therapeutic Effects of Curcumin in Different Disorders
https://www.mdpi.com/2218-273X/12/1/82

The molecular biology and therapeutic potential of Nrf2 in leukemia
https://cancerci.biomedcentral.com/articles/10.1186/s12935-022-02660-5

Inhibition of the Nrf2-TrxR Axis Sensitizes the Drug-Resistant Chronic Myelogenous Leukemia Cell Line K562/G01 to Imatinib Treatments
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885806/

The Dark Side of NRF2: Upregulation of NRF2 as a Mechanism for Resistance to Imatinib In CML
https://ashpublications.org/blood/article/116/21/3401/65923/The-Dark-Sid...

The article "The dark side of curcumin" written by Estefanía Burgos-Morón and others:
https://europepmc.org/article/MED/19830693
is a letter commentary that criticizes the use of curcumin as a potential anti-cancer agent. The authors claim that curcumin has several drawbacks which you cite, such as:

• Curcumin can bind and intercalate into DNA, causing DNA damage and mutations.
• Curcumin can interfere with the activity and metabolism of some drugs, such as tyrosine kinase inhibitors (TKIs), which are used to treat CML and other cancers.
• Curcumin can induce oxidative stress and inflammation, which can worsen the condition of some patients.
• Curcumin can have opposite effects depending on the dose, the cell type, and the experimental conditions.

The authors suggest that curcumin should not be considered as a "curecumin", but rather as a "curse-cumin", and that more rigorous studies are needed to evaluate its safety and efficacy.

However, the article has been challenged by other researchers, who have pointed out some flaws and inconsistencies in the authors' arguments. For example:

• Curcumin does not bind or intercalate into DNA, but rather interacts with DNA through hydrogen bonding and electrostatic forces
https://www.arthritis-health.com/treatment/diet-and-nutrition/do-curcumi....
This interaction does not cause DNA damage or mutations, but rather modulates the expression of some genes involved in cell survival and death

https://www.webmedcentral.com/article_view/4329.

• Curcumin does not interfere with the activity or metabolism of TKIs, but rather enhances their effects by sensitizing cancer cells to apoptosis

http://purl.org/dc/elements/1.1/.

Curcumin can also overcome the resistance of some CML cells to TKIs by targeting different molecular pathways

http://purl.org/dc/terms/.

• Curcumin does not induce oxidative stress or inflammation, but rather reduces them by scavenging free radicals and inhibiting pro-inflammatory cytokineshttps://orcid.orghttps//plus.europepmc.org. Curcumin can also protect normal cells from oxidative damage and inflammation caused by other agents

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.24967.

• Curcumin does not have opposite effects depending on the dose, the cell type, or the experimental conditions, but rather has context-dependent effects that are influenced by multiple factors, such as the bioavailability, the target specificity, and the signaling network of curcumin.

Therefore, the letter commentary "The dark side of curcumin" does not provide conclusive or even strong evidence that curcumin makes CML worse. The research cited in the letter is flawed. On the contrary, there is substantial evidence that curcumin has beneficial effects for CML patients, especially those who are resistant to TKIs or must take a lower dose to avoid adverse events. Curcumin interferes with the nf-Kb and Jak2 pathway (downregulates) absolutely necessary to CML sustaining.

https://pubmed.ncbi.nlm.nih.gov/31033209/

Curcumin is no cure, however, and it does have iron chelating properties necessitating ferritin testing to be sure you have adequate iron (don’t take curcumin at the same time as taking an iron supplement or eating iron rich foods by about 4 hours).
I have been taking Curcumin for more than 10 years and will continue to do so. I remain TKI drug free and “undetected” for bcr-abl for over 3.5 years while all of that time taking Curcumin. Arthritis I was developing 10 years ago (runs in my family) is gone (as long as I keep taking Curcumin). Curcumin is a cox-2 inhibitor similar to aspirin in that regard.
Curcumin, in concert with other nutraceuticals can enhance the cancer fighting action of tyrosine kinase inhibitors and in my case, perhaps, have helped eliminate the need for them (i.e. dasatinib).