When I first dived into the supplements that could help fight cancer, one of those I came across was Zinc. I found a lot of literature indicating that Zinc would indeed represent an useful tool, but also found literature indicating that cancer cells may actually like Zinc. In line with this, there are holistic doctors and naturophats who are recommending the use of Zinc to their cancer patients, while others are totally against that. As a result, although I ordered some bottles of capsules, I decided not to use them. There are so many potential treatments out there, and it would not make sense to use something as long as we do not understand it and its potential is still debated.
However, latter I did a deeper dive into this subject to better understand it and as a result of that I became enthusiastic regarding the potential of Zinc in cancer. As I will further discuss, based on my current understanding taking Zinc alone will not help. But when combined with another drug, Zinc may have a great potential.
Speaking about the potential of Zinc in cancer, a very recent (2017) scientific review from Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, MD, USA, was stating the following: “The absence of the essential and correct understanding of the zinc relationships has resulted in unfounded and misguided criticisms and objections regarding the status and implications of zinc in cancer.” (Ref.) If you want to better understand the relevance of Zinc in cancers, I highly recommend to read the review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183570/
As the review above explains, the misguiding of this field was related to the fact that some scientists were suggesting Zinc actually helps the development of cancer cells, since its depletion in some experiments would stop the development. An example of such study is here (Ref.). Yet, as clarified in another paper (Ref.) and in the review above, these kind of studies may be misleading since they are not representing the status and behavior of cells in the human body, in tissue, but represent extreme conditions only possible in the lab.
When searching the literature, what we will find is that most cancer cells maintain their level of Zinc lower then normal cells (for example prostate cancer, liver cancer (Ref.1, Ref.2), pancreatic cancer (Ref.), etc.), with the exception of breast cancer where it seems to be increased compared to normal cells. As we will see in some of the references below, regardless of the normal level of Zinc in cancer cells, when we push more Zinc than they actually need (Ref.), there is a good chance the cancer cells will be killed. From a cancer development point of view, note that Zinc deficiency is believed to be one road towards getting cancer, typical in developed countries (Ref.).
The Zinc level in most of cancer cells seems to be maintained via a down regulation of the (ZIP) transporters responsible for the transport of Zinc across cellular membrane (Ref.). That means, that we can take as much Zinc supplements as we like, and yet that may never get into the cancer cells at the level required to disrupt their normal function.
So what can we do, if we want to push more Zinc into the cancer cells and disrupt their function?
Fortunately, there is a group of chemicals that are called Zinc ionophores (Ref.). Those chemicals have the capability to bind and transport Zinc inside the cancer cell, even if the Zinc transporters are down regulated in cancer cells. Once inside the cancer cell at a level high enough, it has the potential to stop cell functions, regardless of whether we speak about e.g. prostate cancer, etc. with a low level of zinc or e.g. breast cancer with a high level of zinc, prior to Zinc treatment. And the good news is that Zinc ionophores are widely available, used to treat other human problems, while they are also known for their anti cancer action – even when not using Zinc supplementation. Yet, Zinc supplementation is expected to enhance their action.
Disulfiram is one such Zinc ionophore drug, commonly used as an anti alcohol drug with a long track record of safety in humans (Ref.). As discussed in a previous article (see here) Chloroquine (Ref.) and Clioquinole, both widely available drugs for oral or topical admin., are also Zinc ionophores. I will mainly discuss Disulfiram in the following since its effectivenss is already proven, but other Zn ionophores can be considered as well.
As a side remark, combinations of Zinc and another Zinc ionophore called Pyrithione have a long history of use in shampoos to treat dandruff and seborrhoeic dermatitis and is known to exhibit both antifungaland antimicrobial properties. It can be used as an antibacterial agent against Staphylococcus and Streptococcus infections for conditions such as athlete’s foot, eczema, psoriasis, and ringworm. All the relevant references are in this article on Wikipedia (Ref.).
Here are some studies where Zinc alone or in combination with Zinc ionophores has been shown effective in killing cancer cells in the lab:
- Breast cancer (Ref.) Here is a recent PhD thesis discussing the combination of Disulfiram and Zn in breast cancer as an anticancer approach: Investigation into the effects of zinc on the anti-breast cancer properties of disulfiram https://orca.cf.ac.uk/87744/1/2016WigginsHPhD.pdf
- Melanoma (Ref.) On melanoma there are multiple case reports published. Please see them below.
- Hepatocellular cancer HCC (Ref.) The reference also discussing the relevance of Zinc supplementation to improve the outcome of patients with chronic hepatitis C (Ref.) And here is an article representing a collaboration between a large number of institutions suggesting that Zinc may indeed have a role in preventing liver-cancer development (Ref.)
- Pancreatic cancer (Ref.)
- Prostate cancer (Ref.1, Ref.2, Ref.3, Ref.4)
- Colon cancer (Ref. 1, Ref.2)
- Esophageal cancer (Ref.1, Ref.2)
Other benefits of Zinc:
- enhances the immune system (Ref.1, Ref.2, Ref.3, Ref.4)
- offers protection to patients older than 70 years against the cognitive decline (in Alzheimer’s disease) by decreasing the levels of free copper (Ref.).
- improvement of symptoms in patients suffering from depression (Ref.).
- decreasing the risk of incidence of ocular diseases correlated to aging (Ref.)
- decreasing the incidence of infections in the elderly (Ref.) and anemia patients (Ref.).
- positive impact on fertility (Ref.)
Food containing high level of Zinc: Oysters, Beef, Lamb, Venison, Sesame seeds, Pumpkin seeds, Yogurt, Turkey, Green peas, Shrimp.
Successful case reports on Zinc + Disulfiram in Humans
- Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. https://www.ncbi.nlm.nih.gov/pubmed/15367699
Here is a quote from the article “We also report the first use of disulfiram and Zn2+ to treat advanced stage IV metastatic melanoma in a patient. This was done with approval from the Carolinas Medical Center Institutional Review Board, informed consent was obtained, data were collected prospectively, and the patient has been on no other treatment for melanoma. The subject treated is a 64-year-old woman who presented with a nonoperable central liver metastasis from a T2 ocular melanoma that had been removed 5 years previously. She had developed abdominal pain and was found to have a 2.3 cm right hepatic metastasis and a 5.5 cm central liver metastasis confirmed as recurrent melanoma by biopsy. She declined chemotherapy, interleukin-2 therapy, or liver perfusion. After granting informed consent, she was started on 250 mg/d disulfiram (Antabuse, Wyeth, Madison, NJ) with the largest meal of the day. This dose was increased to 500 mg/d after 1 month. Zinc gluconate (50 mg chelated elemental Zn2+, General Nutrition Center, San Francisco, CA) was also given thrice daily but not concurrent with disulfiram administration. This heavy metal and its dose were chosen for previously demonstrated safety in humans as the preventative treatment for Wilson’s disease. Doses of each agent were those currently recommended for treatment of alcoholism and Wilson’s disease, respectively. On starting the protocol, the patient suffered grade 1 (National Cancer Institute Common Toxicity Criteria, version 2.0) diarrhea, nausea, depression, and malaise. Except for nausea, these side effects resolved within 2 months of continued treatment. Her abdominal pain also completely resolved and she returned to work. After 9 months, disulfiram was reduced to 250 mg/d and her nausea ceased. She has continued on disulfiram 250 mg/d and zinc gluconate 50 mg thrice daily. All laboratory studies have remained normal. Repeat computed tomography and positron emission tomography scans after 3 months of therapy showed a >50% reduction in tumor size (Fig. 10, top). A positron emission tomography scan 12 months after initiating treatment showed the lesions to be stable (Fig. 10, bottom), and the most recent computed tomography scan after 42 months of treatment (Fig. 10, top, far right) shows that residual hepatic disease has remained stable. She continues to be clinically well and physically active after 53 continuous months of therapy.”
And here is a Fig. from the article showing the tumor shrinkage:
- Another case report was presented in the patent: Method of inhibiting ATF/CREB and cancer cell growth and pharmaceutical compositions for same https://www.google.com/patents/US20040019102
Here is a quote from the patent: “a 57 year old woman who had a Clark Level III, 0.73 mm thick melanoma excised from her left back 9 years prior to entering the study. Patient #3 received no adjuvant treatment and developed a left axillary metastasis 4 years later, treated by axillary dissection. The patient received a year of adjuvant alpha interferon and 8 months later was found to have a chest wall and a lung metastasis. The patient was treated with high dose interleukin-2 but then developed additional axillary metastases requiring further dissection and radiation. Patient #3 refused standard chemotherapy. When beginning disulfiram and zinc gluconate, the patient had metastatic disease to the pelvic lymph nodes, left lung, and multiple subcutaneous sites. Initially, patient #3 suffered grade 1 diarrhea, fatigue, malaise, increased anxiety and depression. Diarrhea and malaise completely resolved within 2 months. Anxiety and depression were controlled with medication. Laboratory studies remained normal. Patient #3 temporarily stopped treatment for 5 weeks so that the patient could consume alcohol at a wedding, but resumed treatment at 250 mg disulfiram daily and 50 mg zinc gluconate three times daily and remained clinically stable and free of tumor progression 12 months after first initiating therapy. Interval PET scans showed no new lesions, 3 lung and lymph node mestastases that are stable, resolution of an area of soft tissue metastasis at the right iliac crest, and development of central necrosis in an area of soft tissue metastasis in the posterior left shoulder.”
- Here is the website of a Russian medical doctor and PhD (Dr. Jacob L. Turumin), presenting several cases of successful treatment of melanoma patients, using Disulfiram + Zn + Cu: http://www.drturumin.com/en/Melanoma_en.html
The website includes very clear pictures showing tumor shirinkage after using such treatment in oral and or topical form. He finally concludes that “This algorithm of the pathogenetic treatment may help to decrease mortality and may help to increase a survival of patients with melanoma. Probably it will help to raise the 5 years survival rate up to 50 % in the patients with secondary metastatic melanoma.”
Patent on Disulfiram + Zinc:
Method of inhibiting ATF/CREB and cancer cell growth and pharmaceutical compositions for same (Ref.)
There is provided a method for inhibiting ATF/CREB and cancer cell growth using disulfiram, administered in combination with heavy metals. It was found that disulfiram disrupts transcription factor DNA binding by forming mixed disulfides with thiols within the DNA-binding region, and that this process is facilitated by metal ions. Disulfiram administered to melanoma cells in combination with copper (II) or zinc(II) decreased expression of cyclin A, reduced proliferation in vitro, and inhibited growth of melanoma cells. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism stabilized tumor growth in two of three patients with Stage IV metastatic melanoma, with 12 and 17 month survivals, respectively, to date, and produced a >50% reduction in hepatic metastases in one individual.
Although not including Zinc, but nice to mention, here is a patent on Disulfiram for Breast Cancer:
Use of Disulfiram for Inflammatory Breast Cancer Therapy (Ref.)
Methods, compositions of matter, and kits for treatment of breast cancer, and in particular for inflammatory breast cancer, in a patient are disclosed. The methods can include administering a redox modulating agent to the patient. The redox modulating agent can be disulfiram.
Increasing Reactive Oxygen Species (Ref.) therefore not best to combine with strong anti oxidants.
Another mechanism related to Zn anti-cancer activity was recently found to be connected to the fact that zinc impedes overactive calcium signals in cancer cells, which is absent in normal cells (Ref.1, Ref.2) Interestingly, many anti cancer substances are interfering with intra cellular calcium activity, as I previously discussed here.
For more details on the mechanism please read the enclosed references.
Oral application according to Brar’s paper (Ref.):
- 250 mg/d disulfiram (Antabuse, Wyeth, Madison, NJ) with the largest meal of the day. This dose was increased to 500 mg/d after 1 month.
- Zinc gluconate (50 mg chelated elemental Zn2+,) was also given thrice daily but not concurrent with disulfiram administration.
Oral and topical application according to Dr. Jacob L. Turumin website (this was suggested for melanoma but it can be considered for other cancer types as well):
- Before operation: During 2-4 weeks a patient receives a local treatment (disulfiram plus CuSO4 – drops) and systemic treatment (disulfiram plus ZnSO4 – tablets) for decrease of melanoma cells activity.
- Immediately after the operation a patient receives a local treatment (if possible Esperal which is a sterile form of disulfiram tablets) for a future decrease of melanoma cells activity and formation of local relapse.
- After operation during 1-6 months (maximal period may make up 5 years) a patient can receive a partial local pathogenetic treatment (disulfiram plus CuSO4 – drops) and/or a systemic pathogenetic treatment (disulfiram plus ZnSO4 – tablets) for decrease of risk of melanoma metastases.
- Doses used were disulfiram (500 mg/day) plus zinc sulfate (ZnSO4 – 45 to 90 mg chelated elemental Zn2+ – thrice daily) – essentially same as above
Note: During the Disulfiram usage, the patient needs to stop alcohol usage as side effects will be triggered, since it is used to support detox for alcohol dependence. That is a drawback since no other medication that contains alcohol can be used. Note that some IV treatments (including Curcumin) may contain ethanol.
Better to avoid combining Zinc with Selenium (Ref.)
As prevention we can use 15-30mg Zinc/day with food.
It is known to be a drug with moderate side-effects. Significant side-effects include hepatitis (1 case in 30,000 treated/yr), and neurologic. Rare reports of psychosis and confusional states. Tiredness, headache and sleepiness are the most common. The metabolism of other drugs may be inhibited by disulfiram, increasing their potential for toxic effects.
Drugs known to have adverse effects when used concurrently with disulfiram include amitriptyline, isoniazid, and metronidazole (all with acute changes in mental state), phenytoin, some benzodiazepines, morphine, pethidine, and barbiturates.
Disulfiram (at the pharmacy) and Zinc (at the supplement store) are widely available, are cheap so should be accessible to anyone.
Direct Effect of Zinc on Mitochondrial Apoptogenesis in Prostate Cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465826/
Exposure to zinc induces apoptosis in PC-3 and BPH cells, which accumulate high intracellular levels of zinc, but not in HPR-1 cells, which do not accumulate high levels of zinc. Once initiated, the induction of apoptosis is not reversed by the removal of zinc, i.e., it is an irreversible process. The apoptogenic effect is due to a direct effect of zinc on mitochondria that results in the release of cytochrome c. The cell specificity of zinc induction of apoptogenesis is dependent on the ability of the cells to accumulate high levels of intracellular zinc and on the ability of the mitochondria to respond to the direct effect of zinc.
The Metabolic Phenotype of Prostate Cancer https://www.ncbi.nlm.nih.gov/pubmed/28674679
Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. https://www.ncbi.nlm.nih.gov/pubmed/9609552
The prostate gland of humans and many other animals has the major function of accumulating and secreting extraordinarily high levels of citrate. This specialized metabolic process of “net citrate production” is the result of unique metabolic capabilities of the secretory epithelial cells. Most importantly, in prostate cancer (Pca) the capability for net citrate production is lost. In addition to citrate, the normal and BPH (benign prostatic hyperplasia) prostate also accumulates the highest levels of zinc in the body. As with citrate, in Pca the ability for high zincaccumulation is diminished. These and other correlations between zinc and citrate in the prostate have been indicative of an important role of zinc in the regulation of citrate metabolism in normal and malignant prostate epithelial cells. The link between zinc and citrate metabolism has now been established. The intramitochondrial accumulation of high zinc levels inhibits mitochondrial (m-) aconitase activity, which inhibits citrate oxidation. This essentially truncates the Krebs cycle and markedly decreases the cellular energy (ATP) production normally coupled to citrate oxidation. It is also clear that zinc accumulation in citrate-producing prostate epithelial cells is regulated by testosterone and by prolactin. These relationships form the basis for a new concept of the role of zinc and citrate-related energy metabolism in prostatemalignancy. The inability of malignant prostate cells to accumulate high zinc levels results in increased citrate oxidation and the coupled ATP production essential for the progression of malignancy. The concept offers new approaches to the treatment of Pca.
Metal Ionophores – An Emerging Class of Anticancer Drugs http://onlinelibrary.wiley.com/doi/10.1002/iub.253/pdf
Compounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells
focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based
classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents
Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. https://www.ncbi.nlm.nih.gov/pubmed/25050823
The status of zinc in the development of hepatocellular cancer: An important, but neglected, clinically established relationship https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979811/#R54
Liver cancer (hepatocellular carcinoma, HCC) is increasing worldwide. About 75% of HCC cases result in death generally within one year. The factors responsible for the initiation and progression of HCC remain largely unknown and speculative, thereby impeding advancements in the development of effective therapeutic agents and biomarkers for early detection of HCC. A consistent marked decrease in zinc in HCC tumors compared with normal liver is an established clinical relationship, which occurs in virtually all cases of HCC. However, this relationship has been largely ignored by the contemporary clinical and research community. Consequently, the factors and mechanisms involved in this relationship have not been addressed. Thus, the opportunity and potential for its employment as biomarkers for early identification of malignancy, and for development of a chemotherapeutic approach have been lacking. This presentation includes a review of the literature and the description of important recent and new data, which provide the basis for a concept of the role of zinc in the development of HCC. The basis is presented for characterizing HCC malignancy as ZIP14-deficient tumors, and its requirement to prevent zinc cytotoxic effects on the malignant cells. The potential for an efficacious zinc treatment approach for HCC is described. The involvement of zinc in the predisposition for HCC by chronic liver disease/cirrhosis is presented. Hopefully, this presentation will raise the awareness, interest, and support for the much needed research in the implications of zinc in the development and progression of HCC.
Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma. https://www.ncbi.nlm.nih.gov/pubmed/21613827
This report provides the clinical foundation for further mechanistic studies that will provide important insight into pancreatic carcinogenesis, and can lead to the development of effective early biomarkers and effective therapeutic agents for pancreatic cancer.
Zinc transporters and dysregulated channels in cancers https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199720/
As a nutritionally essential metal ion, zinc (Zn) not only constitutes a structural element for more than 3000 proteins but also plays important regulatory functions in cellular signal transduction. Zn homeostasis is tightly controlled by regulating the flux of Zn across cell membranes through specific transporters, i.e. ZnT and ZIP family proteins. Zn deficiency and malfunction of Zn transporters have been associated with many chronic diseases including cancer. However, the mechanisms underlying Zn regulatory functions in cellular signaling and their impact on the pathogenesis and progression of cancers remain largely unknown. In addition to these acknowledged multifunctions, Zn modulates a wide range of ion channels that in turn may also play an important role in cancer biology. The goal of this review is to propose how zinc deficiency, through modified Zn homeostasis, transporter activity and the putative regulatory function of Zn can influence ion channel activity, and thereby contribute to carcinogenesis and tumorigenesis. This review intends to stimulate interest in, and support for research into the understanding of Zn-modulated channels in cancers, and to search for novel biomarkers facilitating effective clinical stratification of high risk cancer patients as well as improved prevention and therapy in this emerging field.
The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots https://www.ncbi.nlm.nih.gov/pubmed/16700911
The genetic/metabolic relationships in normal prostate glandular epithelium are driven by the unique function to accumulate and secrete citrate. The genetic/metabolic transformation of the prostate malignant cells is driven by the metabolic/bioenergetic, growth/proliferative, and invasive/migration requirements of the malignant process. Zinc is critical to these relationships. An understanding of these genetic/metabolic relationships provides new directions and opportunities for development of regimens for the prevention and treatment of prostate cancer. Important insight into the genetic/metabolic requirements of the prostate malignant process is now evolving. Most importantly at this time, an appreciation and recognition of the genetic/metabolic significance and implications in the development of prostate malignancy is imperative; and much needed research in this area is essential. Hopefully, this review will help to achieve these goals.
Circulating copper and zinc levels and risk of hepatobiliary cancers in Europeans https://www.ncbi.nlm.nih.gov/pubmed/28152549
Zinc may have a role in preventing liver-cancer development, but this finding requires further investigation in other settings.
Zinc, aging, and immunosenescence: an overview https://www.ncbi.nlm.nih.gov/pubmed/25661703
Zinc plays an essential role in many biochemical pathways and participates in several cell functions, including the immune response. This review describes the role of zinc in human health, aging, and immunosenescence. Zinc deficiency is frequent in the elderly and leads to changes similar to those that occur in oxidative inflammatory aging (oxi-inflamm-aging) and immunosenescence. The possible benefits of zinc supplementation to enhance immune function are discussed.
Zinc homeostasis and immunosenescence https://www.ncbi.nlm.nih.gov/pubmed/25022332
For more than 50 years, zinc is known to be an essential trace element, having a regulatory role in the immune system. Deficiency in zinc thus compromises proper immune function, like it is observed in the elderly population. Here mild zinc deficiency is a common condition, documented by a decline of serum or plasma zinc levels with age. This leads to a dysregulation mainly in the adaptive immunity that can result in an increased production of pro-inflammatory cytokines, known as a status called inflamm-aging. T cell activation as well as polarization of T helper (Th) cells into their different subpopulations (Th1, Th2, Th17, regulatory T cells (Treg)) is highly influenced by zinc homeostasis. In the elderly a shift of the Th cell balance towards Th2 response is observed, a non-specific pre-activation of T cells is displayed, as well as a decreased response to vaccination is seen. Moreover, an impaired function of innate immune cells indicate a predominance of zinc deficiency in the elderly that may contribute to immunosenescence. This review summarizes current findings about zinc deficiency and supplementation in elderly individuals.
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