Copper Chelation and Cancer (AugSept 2013) Townsend Letter for Doctors & Patients

From the Townsend Letter
August / September 2013

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Environmental Medicine Update
Copper Chelation and Cancer
by Marianne Marchese, ND
www.drmarchese.com

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Introduction
There have been several articles recently published about the effects of copper on cancer and the results of copper chelation as a useful cancer therapy. This information is not new, and studies date back to the early 1980s describing this correlation. What is new is a better understanding of the mechanism involved and benefits of chelation with cancer. For the patient and practitioner new to the world of environmental medicine and chelation, this concept may need to be explored in greater detail.

Copper
Copper is a metal that occurs naturally in the environment, and also in plants and animals. It is necessary for us to live. Low levels of copper are essential for maintaining good health. Acute exposure can cause harmful effects such as irritation of the nose, mouth, and eyes; vomiting; diarrhea; stomach cramps; nausea; and even death. Copper is used to make many different kinds of products such as wire, plumbing pipes, and sheet metal. US pennies made before 1982 are made of copper, while those made after 1982 are only coated with copper. Humans are exposed to copper from breathing air, drinking water, eating foods, or having skin contact with copper, particulates attached to copper or copper-containing compounds.¹

Everyone must absorb small amounts of copper every day because copper is essential for good health. Copper plays a pivotal role in cell physiology as a catalytic cofactor in the redox chemistry of mitochondrial respiration, iron absorption, free-radical scavenging, and elastin cross-linking. High levels of copper can be harmful and linked to Menkes syndrome and Wilson's disease, rheumatoid arthritis, gastrointestinal ulcers, epilepsy, diabetes, and cancer.² Copper toxicity is due to its ability to produce reactive oxygen species (ROS), displace other metal ions, peroxidize lipids, and directly cleave DNA and RNA.³

Copper and Cancer
High copper levels have been found in many types of human cancers, including prostate, breast, colon, lung, and brain.⁴ Angiogenesis, the formation of new capillaries from existing vasculature, is a critical process in normal physiology as well as cancerous tumor formation and growth. Copper is an important cofactor for angiogenesis. The role of copper in angiogenesis formation was first discovered in animal models in the 1980s. (Rajuet et al. 1982, Ziche et al. 1982). Angiogenesis displays a unique sensitivity to bioavailable copper. Numerous molecules important to angiogenesis regulation have been shown to be either directly or indirectly influenced by copper levels the body.⁵ Endothelial cell migration is an essential early step in angiogenesis. Copper has been shown to induce migration of endothelial cells and a heparin-copper complex has been shown to stimulate capillary migration in vitro as well as angiogenesis in vivo.⁶ Copper-binding molecules are nonangiogenic when free of copper, but they become angiogenic when bound to copper.⁷

Serum and tumor copper levels are significantly elevated in a variety of cancers, including breast, ovarian, gastric, bladder, and leukemia. A 2012 study of patients in China with bladder cancer showed elevated serum copper levels compared with controls.⁸ Another recent study looked at copper levels in neoplastic breast tissue and found higher levels compared with normal tissues.⁹ It also investigated whether copper levels could be used as a prognostic factor in breast cancer. The prognostic factors assessed were age, menstrual status, tumor size, histological grade, staging, lymph node involvement, estrogen and progesterone receptors, and HER-2 status. Correlation between copper and tumor size, histological grade, TNM staging, and lymph node status was conducted as well. Patients with positive expression for copper presented a poor overall survival. Again, copper has a crucial role in the angiogenic mechanism, and tumors that become angiogenic exhibit a high metastatic potential, a major cause of mortality in patients with breast cancer.⁹

Blood and tissue copper levels are an important marker for patients with cancer; however, blood tests can show high copper levels even when there is little copper in the tissues. This is why blood ceruloplasmin (Cp) level is also important. Cp is a copper-containing protein secreted by the liver into the blood. The copper in Cp accounts for about 90% of the total plasma copper. As copper availability to the liver decreases, the liver decreases production and secretion of Cp. Thus, plasma Cp is a good marker of body copper status.⁶

Copper Chelation
Antiangiogenic agents are an important part of conventional cancer therapies. New compounds are always being tested for their antiangiogenic role, including those that bind copper to inhibit angiogenesis.¹⁰ Since copper has been found to be a major growth nutrient required for angiogenesis, the consideration arose that limiting copper levels in the body could help control the growth of malignant tumors. Several studies have investigated if lowering copper levels can be used as an antiangiogentic therapy for cancer.

A recent study which generated a lot of interest in this topic used the anticopper drug tetrathiomolybdate in patients with triple-negative breast cancer. Tetrathiomolybdate is a copper chelation drug that has been used in patients with Wilson's disease for years. This phase II clinical trial showed that patients with triple-negative breast cancer had a decreased recurrence when using the copper-depleting drug.¹¹ In fact, four of the study participants with a history of metastatic triple-negative breast cancer have had long-term benefit, remaining disease free for between 3 and 5½ years. Also, study participants with other forms of high-risk for relapse breast cancers — either stage III or stage IV — without evidence of disease after treatment have also fared well. The progression-free survival rate among these 29 patients in the study has been 85% to date.¹¹ This study reinforced that copper is essential to the metastatic process. It is a key component of enzymes that help turn on angiogenesis in the tumor microenvironment, and it also appears to play a role in directing cancer cell migration and invasion, according to researchers.

Copper-chelating agents appear to be useful in cancer treatment in ways unrelated to angiogenesis; they can also be cytotoxic to cancer cells. D-penicillamine (D-pen), another copper-chelating agent, can generate intracellular reactive oxygen species (ROS) and be cytotoxic to human leukemia and breast cancer cells.¹² A 2010 study showed that copper chelation using tetrathiomolybdate improves cisplatin efficacy in a mouse model of cervical cancer, enhances cisplatin killing of human ovarian and cervical cancer cells, increases cisplatin-DNA adduct levels in cancerous but not in normal tissues, impairs angiogenesis, and improves therapeutic efficacy.¹³

As mentioned earlier, plasma Cp is a good surrogate marker for total body copper status. A 2004 study using the copper chelator tetrathiomolybdate in animals with cancer showed a suppression of Cp levels, a 70% reduction in tumor microvessel count, inhibition of angiogenesis, and suppression of the human VEGF expressed in the tumor as well as the mouse VEGF detected in the plasma.¹⁴

Older studies also show benefits of using copper-chelating agents in cancer. In an animal model of head and neck cancer, tetrathiomolybdate (TM) has shown efficacy in suppressing tumor growth, and Cp levels were reduced by 28% in the treated animals.¹⁵ Copper chelation also suppresses tumor growth in two animal models of breast cancer.¹⁶ In 2003, results of a phase II trial of TM in advanced kidney cancer were published. Fifteen patients with metastatic kidney cancer who had not responded to IL-2 or were not eligible for IL-2 were treated with TM. All patients were able to achieve the target Cp level of 5 to 15 mg/dl. Of the 13 patients evaluable for response, 4 (31%) had stable disease for at least 6 months.¹⁷

A 2010 study on head and neck squamous cell carcinoma (HNSCC) showed that tetrathiomolybdate can act long term as a suppressor of vascularity and inhibit the growth of metastasis of HNSCC. Tetrathiomolybdate treatment drastically suppressed the development of lung metastases.¹⁴

Although many of these studies cited above are in animal models, cell cultures, and phase I and II human clinical trials, it is clear there is benefit to copper chelation in cancer. Copper depletion therapy is shown to be safe and nontoxic. The main side effect is anemia, which can be easily monitored. More research and human clinical trials on long-term outcomes of copper depletion therapy in cancer need to be conducted.

Summary
Copper is an essential mineral required for growth, the production of red and white blood cells, and many other cellular functions. The role of copper in cancer promotion through inflammation and angiogenesis is now well understood. Copper depletion therapy, or chelation, appears to have benefits in cancer treatment and as an antiangiogenic agent. There is an important link between Cp levels and copper. Cp is a good marker of body copper status. Levels can be used to determine efficacy of copper chelation therapy. Ongoing phase II studies as well as future trials will further define the role of copper chelation in cancer treatment.

Notes
1.   Agency for Toxic Substances and Disease Registry (ATSDR). 2004. Toxicological Profile for Copper. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
2.   Turnlund JR et al. Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope copper-65. Am J Clin Nutr.1989;49(5):870–878.
3.   Halliwell, B, Gutteridge J.M. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol.1990;186:1–85.
4.   Daniel KG et al. Copper storage diseases: Menkes, Wilson's, and cancer. Front Biosci. 2004;9:2652–2662.
5.   Finney L et al. Copper and angiogenesis: unravelling a relationship key to cancer progression Clin Exp Pharmacol Physiol. 2009;36(1):88–94.
6.   Goodman VL, Brewer GJ, Merajver SD. Copper deficiency as an anti-cancer strategy. Endocr Relat Cancer. 2004;11(2),:255–263
7.   Brem S. Angiogenesis and cancer control: from concept to therapeutic trial. Cancer Control J. Sept/Oct 1999;6(5). Available at http://moffitt.usf.edu/CCJRoot/v6n5/article2.htm. Accessed May 5, 2013.
8.   Guo KF et al. Variation of urinary and serum trace elements (Ca, Zn, Cu, Se) in bladder carcinoma in China. Asian Pac J Cancer Prev. 2012;13(5):2057–2061.
9.   Silva MP et al. Trace elements as tumor biomarkers and prognostic factors in breast cancer: a study through energy dispersive x-ray fluorescence. BMC Res Notes. 2012;6(5):194
10. Sproull M, Brechbiel M, Camphausen K. Antiangiogenic therapy through copper chelation. Expert Opin Ther Targets. 2003;7(3):405–409.
11. Jain S et al. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Ann Oncol. 2013. Epub February 13, 2013.
12. Gupte A, Mumper RJ. Copper chelation by D-penicillamine generates reactive oxygen species that are cytotoxic to human leukemia and breast cancer cells. Free Radic Biol Med. 2007;43(9):1271–1278.
13. Ishida S et al. Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell. 2010;17(6):574–583
14. Hassouneh B et al. Tetrathiomolybdate promotes tumor necrosis and prevents distant metastases by suppressing angiogenesis in head and neck cancer. Mol Cancer Ther. 2007;6:1039.
15. Cox CD et al. The role of copper suppression as an antiangiogenic strategy in head and neck squamous cell carcinoma. Laryngoscope. 2001;111:696–701.
16. Pan Q et al. Antiangiogenic tetrathiomolybdate enhances the efficacy of doxorubicin against breast carcinoma. Mol Cancer Ther. 2003;2:617–622.
17. Redman BG et al. Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clin Cancer Res. 2003:9;1666–1672.

Dr. Marchese is the author of 8 Weeks to Women's Wellness: The Detoxification Plan for Breast Cancer, Endometriosis, Infertility, and other Women's Health Conditions. Dr. Marchese graduated from the National College of Naturopathic Medicine in 2002. She maintains a private practice in Phoenix, Arizona, and teaches gynecology at Southwest College of Naturopathic Medicine.

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