Copper promotes the formation of blood vessels, including those that supply tumors. Depleting copper can deprive the tumor of its suppliers.
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This section does not replicate the other information on this topic but provides additional details or context most relevant to professionals.
Notable preclinical evidence is described. Clinical evidence is summarized in How can copper chelation help you? What the research says ›
Improving treatment outcomes: preclinical evidence
- In preclinical models, tetrathiomolybdate decreased metastases to lungs, LOX activity, and collagen crosslinking in MDA-LM2-luciferase cells on mice.1Chan N, Willis A et al. Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research. 2017 Feb 1;23(3):666-676.
- Anti-angiogenic activity with TM in animals, with a favorable toxicity profile in preliminary clinical studies2Khan G, Merajver S. Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm. Expert Opinion on Investigational Drugs. 2009;18(4):541–548; Brewer GJ. Anticopper therapy against cancer and diseases of inflammation and fibrosis. Drug Discovery Today. 2005;10(16):1103–1109.
- Inhibits tumor growth and substantially improved survival of triple-negative breast cancer in mice3Cui L, Gouw AM et al. Mitochondrial copper depletion suppresses triple-negative breast cancer in mice. Nature Biotechnology. 2021 Mar;39(3):357-367.
- Anticancer effects in prostate cancer cells from pyrrolidine dithiocarbamate (PDTC) but not TM4Chen D, Peng F et al. Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis. Frontiers in Bioscience. 2005 Sep 1;10:2932-9.
- D-Pen inhibits gliosarcoma and melanoma tumor growth in animals and is an effective antiangiogenic agent in gliomas in rats.5Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews. 2009;35(1):32–46.
- Colon cancer:
- Antitumor activity in human colon cancer cells grafted onto mice6Fatfat M, Merhi RA et al. Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species. BMC Cancer. 2014;14:527.
- Affected proliferation, survival, and migration in colorectal cancer cells with BRAF mutation, a gene mutation which may increase the growth and spread of cancer cells. Copper chelation also decreased the cloning potential of BRAF cells otherwise resistant to drugs targeting the BRAF mutation.7Baldari S, Di Rocco G et al. Effects of copper chelation on BRAFV600E positive colon carcinoma cells. Cancers (Basel). 2019;11(5):659.
- Melon extracts, especially melon peel aqueous extract, showed copper-chelating properties in lab studies.8Rolim PM, Fidelis GP et al. Phenolic profile and antioxidant activity from peels and seeds of melon (Cucumis melo L. var. reticulatus) and their antiproliferative effect in cancer cells. Brazilian Journal of Medical and Biological Research. 2018;51(4):e6069.
- Copper chelators plus iron chelators combined with DHA and 5-FU in colorectal cancer cells overcame drug resistance through apoptosis.9Yu N, Zhu H et al. Combination of Fe/Cu -chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer. Oncotarget. 2017;8(31):51478–51491.
Optimizing your body terrain: preclinical evidence
- Antioxidant: Excess copper is a potent oxidant, causing the generation of harmful reactive oxygen species (ROS) in cells. These ROSs are known to drive cancer development and growth.10Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews. 2009;35(1):32–46.
- Immune function: Improved immune pathway response in animals11Khan G, Merajver S. Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm. Expert Opinion on Investigational Drugs. 2009;18(4):541–548.
- Anti-inflammatory effects in animal studies12Brewer GJ. Anticopper therapy against cancer and diseases of inflammation and fibrosis. Drug Discovery Today. 2005;10(16):1103–1109.
Modes of action
Copper levels in blood plasma are significantly increased in neoplasias in the stomach, large intestine and lungs.13Scanni A, Licciardello L, Trovato M, Tomirotti M, Biraghi M. Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung. Tumori. 1977;63(2):175–180. As disease progresses, copper levels further increase, and they decline with remission.14Scanni A, Tomirotti M et al. Variations in serum copper and ceruloplasmin levels in advanced gastrointestinal cancer treated with polychemotherapy. Tumori. 1979;65(3):331–338.
Intratumoral copper levels influence PD-L1 expression in cancer cells, and copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1.15Voli F, Valli E et al. Intratumoral copper modulates pd-l1 expression and influences tumor immune evasion. Cancer Research. 2020 Oct 1;80(19):4129-4144.
The inflammatory response induces copper uptake through an IL-17-STEAP4-XIAP axis, promoting colon tumorigenesis.16Liao Y, Zhao J et al. Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis. Nature Communications. 2020 Feb 14;11(1):900.
Naturopathic physician Mark Bricca, ND, MAc, June 29-30, 2021: Tetrathiomolybdate is off-patent, and it has not recently been favored by regulatory agencies as a result. The FDA currently has it in a gray area with respect to compounding. Insurance virtually never covers it, since it is compounded and considered “experimental.” (And there’s been little interest in funding clinical trials using TM in cancer, since it is off-patent.)
While the wonderful doctor Mark Rosenberg, MD, uses TM more commonly as part of his treatment for people with active cancer, clinically I and other practitioners I know tend to rely on it primarily for recurrence prevention in higher risk cancers. Once a cancer is in remission, for recurrence to occur, a nascent tumor must flip what’s referred to as the “angiogenic switch” in order to grow any larger than about 2 cubic millimeters, which is the limit for passive diffusion of nutrients and wastes via the extracellular matrix. Half a dozen of the early angiogenic factors, including VEGF and FGF, are highly copper-dependent, so we can intentionally and skillfully use TM to selectively chelate copper stored in tissues in order to limit the supply available for any cancer-related angiogenesis.
Nothing is all good or all bad, and copper is needed in bone marrow for hematopoiesis, for collagen formation, and for proper neurological function. So, in practice, I consider using TM in patients at high-risk of cancer recurrence and in those for whom good treatment options do not exist in case of recurrence (I’ve had some good success preventing recurrence in very high risk osteosarcoma, and I plan to start this therapy soon in an eight year old, just in remission from extremely high risk Ewing’s sarcoma). Linda Vahdat, MD, has been leading clinical trials using TM in women at high risk of breast cancer relapse (TNBC and stage III cancers), and her findings over the years have consistently been favorable and in alignment with our collective (mine and colleagues’) clinical experience.
TM is compounded into 20 mg capsules, which have a relatively short shelf life after exposure to air (it oxidizes pretty readily and loses potency). The dose gets titrated to control serum ceruloplasmin (Cp), which is the primary copper carrying protein in the blood. Most labs’ lower limit of normal is about 18mg/dL for copper and, for cancer recurrence prevention, we typically seek to maintain copper in a range between 10 and 15mg/dL. I’ll go lower in higher risk situations, and I am more conservative in folks who have risk for development of cytopenias (such as people who recently completed myelosuppressive chemo, men on long-term ADT). We check copper at baseline and then monitor copper and CBC at least every 4 weeks. A typical induction dose, depending on baseline copper and level of urgency, is 40mg TM orally at the beginning of meals 3x/daily, plus 60mg nightly at bedtime (180mg/daily). Once target copper is achieved, the dose is adjusted for maintenance, and ideally the therapy is maintained for a sum total of 3 years at target copper. I care for two patients, one sarcoma patient and one TNBC patient, who have been on TM therapy for roughly 5 years while maintaining high-risk remission with no adverse effects from treatment.
Adverse effects, in my experience, are pretty rare, and they can include cytopenias in any cell line, development of mild peripheral neuropathy (pins/needles), leg cramping, and some wrinkling of skin. All adverse effects, when they arise, are dose-dependent, and typically amenable to dose adjustment and/or supportive strategies. In practice, I’ve not seen people, even those at high recurrence risk, go on to have recurrences after at least a year at target copper. The challenge, sometimes, is keeping them in durable remission for the first year of treatment, which seems to be the length of time required to adequately “de-copper” any potential tumor microenvironment.
Over the years, I’ve seen some peripheral neuropathy develop in less than 10% of people on long-term TM therapy. Typically, it’s been managed well with dose adjustment to maintain copper a little higher and, if symptoms are significant, we’ll also bring in the “usual” support for peripheral nerves (ALA, B6, etc). I’ve had one or two people choose to go off TM due to development of peripheral neuropathy, and in these instances the neuropathy has completely resolved within a month or so of cessation of treatment. It is good to watch this, as one would not want significant neuropathy to go unrecognized/treated. It’s a known possible side effect in a minority of TM users, and manageable when it arises, so it’s not something we worry about, just something to be aware of.
Peripheral neuropathy from TM, when it develops, typically takes time—I’ve not seen it arise until after a person has been on TM for a year or more. If a person had peripheral neuropathy, more commonly from cisplatin or oxaliplatin, then I would certainly watch more for this possibility. Peripheral neuropathy, while still possible, is substantially rarer with carboplatin—so while I would still be aware of the possibility, I would be less mindful of it than I would be given use of cis or oxaliplatin.
Of note, there is also good data on TM/copper chelation synergizing with platinum chemo treatments. This is a different use, however, and one needs to take care with lowering copper too much during chemo treatment, primarily in order not to place too much pressure on marrow hematopoiesis. Concurrent TM use with platinum chemo requires care, as platinum is myelosuppressive and copper reduction can predispose to cytopenias since copper is needed in marrow for blood cell production. So, in the rare instances that I combine these therapies, I simply go easier on dosing and perhaps aim to lower copper to just below normal, something like 16-18mg/dL, while carefully monitoring for any synergistic stresses in the CBC. I don’t do this often but, given data suggesting synergy between platinum and copper reduction, it’s a worthwhile consideration for some patients who are willing to try the treatment for potentially greater therapeutic benefit.
There are nuances to TM therapy in clinical practice, and they’re relatively easy to learn and straightforward to implement. I have found it to be an incredibly valuable resource for people!
See further commentary regarding use by professionals in How do experts use copper chelation? ›
Resources for professionals
Tsang T, Posimo JM et al. Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nature Cell Biology. 2020 Apr;22(4):412-424.
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