Could zinc dipicolinate be used to “smuggle” zinc into prostate cancer cells?
Zinc dipicolinate shows promise as a potential agent for transporting zinc into prostate cancer cells, offering a practical approach for therapeutic exploration.
Viability of prostate cancer may require exclusion of zinc
Prostate epithelium is characterized by high intracellular levels of zinc, particularly within the mitochondria[1]. This intra-mitochondrial zinc is believed to promote the proper function of prostate epithelium by inhibiting aconitase activity, thereby causing an accumulation of citrate in the Krebs cycle[2,3]. Much of this citrate is exported into the seminal fluid, where it serves as an energy substrate for spermatozoa.However, malignantly transformed prostate epithelium is far lower in intracellular zinc, reflected greatly diminished expression or activity of transporter proteins - ZIP1, ZIP2, and ZIP3 - that import zinc[4-8]. This loss of intracellular zinc appears to be essential to the viability of the transformed cells, as measures which restore high intracellular zinc levels - exposure to high extracellular zinc, or treatment with zinc ionophores such as pyrithione or clioquinol - slows their proliferation and up-regulates cell death[8-11]. In vivo, continual intravenous infusion of zinc, injection of zinc acetate directly into tumors, or parenteral administration of the zinc ionophore clioquinol has notably slowed the growth of human prostate cancers in nude mice[12-14]. In particular, administration of clioquinol was associated with an 85% growth retardation of a ZIP-1- deficient human prostate cancer[14].
In a range of human prostate cancer cells lines, increasing intracellular zinc with zinc pyrithione led to necrotic cell death associated with plummeting ATP levels, oxidative stress, and activation of ERK and PKC[10]. The antioxidants N-acetylcysteine (NAC) and trolox protected against cell death in this system; NAC, but not trolox, likewise blunted the decline in ATP. Since prostate epithelium tends to concentrate zinc in mitochondria, it would be of interest to know whether excessive zinc uptake by mitochondria mediates the oxidative stress and reduction in ATP seen after prostate cancer cells are exposed to zinc pyrithione. In addition to inhibiting aconitase activity, zinc is also capable of inhibiting complex III of the respiratory chain, with a Ki of about 100 nmol/L[15-18].
Could malignant transformation of prostate epithelium somehow sensitize their mitochondria to the toxic impact of excessive zinc? The mitochondria of cancer cells are prone to structural abnormalities - possibly reflecting mutations in mitochondrial or nuclear DNA - which increase their propensity to produce superoxide[19,20]. Defects of the mitochondrial respiratory chain or of ATP synthase activity that moderately boost mitochondrial superoxide generation can be expected to promote cellular proliferation, angiogenesis, and mutagenesis; hence, they may act as tumor promoters, in which case these defects would be selected for[20-23]. The exceptionally high mitochondrial zinc levels of prostate epithelium presumably reflect increased expression or activity not only of ZIP1, but also of one or more zinc transporters -possibly ZnT2 - which import zinc into the mitochondrial inner matrix[24]. In mammary epithelial cells, ZnT2 transports zinc into mitochondria, and over-expression of this protein lowers cellular ATP levels and oxygen consumption, and promotes apoptosis; oxidant production was not measured in this study[24].
If this increased intramitochondrial transport of zinc is maintained in transformed prostatic epithelial cells, then high mitochondrial zinc levels might interact with the mitochondrial abnormalities typical of cancer to induce severe dysfunction: excessive production of superoxide, decreased production of ATP, and further mitochondrial structural damage. This sequence of events could evidently be prevented by down-regulation of ZIP1 - which is what in fact is observed in transformed prostate epithelium.
In light of the utility of parenteral clioquinol for controlling growth of a prostate cancer in nude mice, it has been suggested that oral clioquinol could have potential as a therapeutic alternative for prostate cancer control. While it might indeed be the case that some sufficiently modest dose of clioquinol could prove useful in this regard, past clinical experience with oral administration of clioquinol as a fungicide or as a treatment for acrodermatitis enteropathica has been complicated by its association with subacute myelo-optic neuropathy, characterized by peripheral neuropathy and blindness[25,26]. Ten thousand patients in Japan were afflicted with this syndrome until oral use of clioquinol was discontinued in Japan. Hence, clioquinol is now available solely for topical use. The zinc-clioquinol chelate has been shown to lead to rapid mitochondrial damage and loss of mitochondrial membrane potential in a melanoma-derived cell line, possibly explaining the clinical toxicity of clioquinol[27].
Zinc dipicolinate may act as a zinc transporter
However, an alternative strategy for boosting the intracellular zinc levels of clinical prostate cancer may be at hand. Zinc dipicolinate is a readily-available nutraceutical, originally patented by the U.S. Department of Agriculture, in which zinc is chelated by two molecules of the natural tryptophan metabolite picolinic acid; 4 coordination positions of zinc are occupied by picolinic acid in this complex. There is reason to suspect that, at least at neutral pH, zinc dipicolinate is sufficiently stable to carry zinc across bilipid layers. When children with acrodermatitis enteropathica (AE) were treated with either zinc dipicolinate or zinc sulfate, the dose of zinc required to prevent exacerbations of this disorder was found to be one-third as high with zinc dipicolinate, as opposed to zinc sulfate[28]. AE is a hereditary zinc deficiency syndrome in which those afflicted are heterozygous for loss of function of ZIP4, the chief zinc importer expressed by the apical membranes of enterocytes[29,30]. The superior utility of zinc dipicolinate in this syndrome, as opposed to forms of zinc that ionize readily (such as zinc sulfate), seems likely to reflect the ability of the zinc dipicolinate chelate to carry zinc across enterocyte membranes in the absence of zinc transporter proteins. Furthermore, in healthy human subjects, when zinc was administered at 50 mg daily as either zinc dipicolinate, zinc citrate, or zinc gluconate, zinc dipicolinate was shown to have a significantly greater impact on zinc levels in erythrocytes, hair, and urine[31]. When nursing rat mothers were fed zinc as either dipicolinate or acetate, the zinc content of the kidney or liver of nursing pups was higher after the dipicolinate supplement[32].If zinc dipicolinate is sufficiently stable and lipophilic to “smuggle” zinc into enterocytes lacking ZIP4, might it not also be able transport zinc into prostate cancer cells lacking ZIP1 activity? This possibility could be readily tested in prostate cancer cell cultures and, if preliminary results are promising, in nude mice xenografted with human prostate cancer. The possibility that zinc dipicolinate supplementation might also have potential for prevention of prostate cancer might also be envisioned, as reduction in intracellular zinc is believed to arise at an early stage of prostate cancer evolution[33].
While therapies which boost intracellular zinc in prostate cancer might at best be expected to slow prostate cancer progression, the fact that such therapy might boost oxidative stress and lower ATP levels in prostate cancer cells raises the possibility that preceding zinc therapy might render prostate cancer more sensitive to hyperthermia and/or high-dose intravenous ascorbate[34]. The selective susceptibility of cancer cells to high extracellular levels of ascorbate - which generate a high flux of hydrogen peroxide into the these cells - may reflect increased cancer production of superoxide, which can interact with hydrogen peroxide in a transition metal-catalyzed reaction to generate deadly hydroxyl radicals[34,35]. And the lethality of whole body-tolerable hyperthermia (42 °C) to cancer cells may be potentiated by hydrogen peroxide; conversely, overexpression of mitochondrial superoxide dismutase protects a prostate cancer cell line from 43 °C hyperthermia[36-39]. Mitochondrial superoxide production by zinc-treated cancer cells might be potentiated by concurrent treatment with dichloroacetate, which can increase the availability of pyruvate to mitochondria by inhibiting pyruvate dehydrogenase kinase; the latter is highly active in many cancers owing to up-regulated hypoxia-inducible factor-1 activity[34,40,41].
Unlocking Zinc's Potential to Fight Cancer - Cancer Treatments - from Research to Application
Background: 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...
www.cancertreatmentsresearch.com
Unlocking zinc’s potential to fight cancer
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 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. Ethambutol, a drug used to treat tuberculosis is also a Zinc ionophore (Ref.1, Ref.2). 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.).
An Anti-Cancer Compound Hiding in Front of Us: Gluconate - Cancer Treatments - from Research to Application
Gluconate, a cheap, available and harmless substance I recently came across this scientific article reference by one of the active members of this website (J) and realised that something very valuable was hidden in there. In this article, the authors are discussing Gluconate. Their research...
www.cancertreatmentsresearch.com
Gluconate, reduces intracellular citrate
Citrate plays a central role in the metabolism of cancer cells (Ref.). Citrate is the primary substrate for fatty acid synthesis, cholesterol production and contributes to the amino acid synthesis. In addition, it has impact on many other intra-cellular processes such as those discussed here (Ref.) as it is the primary “fuel” for the mevalonate pathway (next to acetate).Cells have two major sources of Citrate:
- Extracellular Citrate received through the blood supplies, with it’s origin in our diet, and
- Citrate produced inside the cells.
Contrary to this approach, other scientist have suggested that another effective way to fight cancer is to lower the Citrate available for tumors. That would reduce fatty acid synthesis, cholesterol production and the amino acid synthesis. In line with this, recently, Dr. Maria E. Mycielska, et al. observed that extracellular Citrate is taken up by cancer cells through a plasma membrane Citrate transporting protein more than in normal tissue. They have also found that decreased blood Citrate levels is associated with patients presenting tumors such as those in the lung, bladder, and pancreas (Ref.). Furthermore, the scientists have found that:
- tumors demand even more citrate when they are in hypoxic area where typical nutrients are harder to find – indeed it is known that citrate transport is stimulated by acidification of extracellular pH (Ref.).
- plasma membrane citrate transporting protein is even more expressed in advanced tumors and metastases
- in line with the above, the presence of extracellular citrate raised the level of (unlabeled citrate) in the cells
- citrate consumption lead to a reduction of glucose and glutamine uptake by the cancer cells (Ref.)
Furthermore, the authors demonstrated that the application of Gluconate on cancer cells blocks extracellular Citrate influx and as a result reduces the tumor growth. As expected, the tumor growth reduction was not only effective on prostate cancer cells but also pancreatic cells. However, because plasma membrane Citrate transporting protein is highly expressed in most cancer types and even more in the aggressive ones, the authors expect that Gluconate could reduce the tumor growth in most cancer types. (Ref.)
With this, the scientific team has demonstrated a new way to fight cancer, that lowers the intracellular Citrate with inhibitors of Citrate membrane cell transporters responsible for the absorption of Citrate from the extracellular space.
The publication of these findings, triggered a discussion in the academic space regarding the two different apparently contradictory approaches to kill cancer: one that has been discussed before (Ref.1, Ref.2), focused on increasing intracellular Citrate, and this one discussed here focused on decreasing intracellular Citrate. Here is, on short, the answer of the authors:
“Although these approaches seem contradictory, they are actually based on the same ability of cancer cells to specifically import extracellular citrate. Both the “low” and “high” citrate uptake approaches do make sense, because low uptake limits citrate availability for critical cancer cell metabolic processes such as fatty acid synthesis, and high intracellular citrate levels inhibit glycolysis and disturb other cellular functions, which are also important for cancer cells” (Ref.)
Anti cancer results in humans after the application of Gluconate
The fact that Gluconate inhibits Citrate absorption into the cell is new and as a result there is no case report directly focused on Gluconate. However, the authors of the paper above have investigated the literature and have publish a new paper entitled “Potential Use of Gluconate in Cancer Therapy” (Ref.). In this papers the authors, based on various arguments, suggest that Gluconate may be the one responsible in achieving the positive results in the fallowing cases:- Treatment of acute lymphocytic leukemia using zinc adjuvant with chemotherapy and radiation–a case history and hypothesis (Ref.).Here, great results were obtained in a case of a 3-year-old girl, who received Zn gluconate next to the chemo. While the results were attributed to Zn, the authors suggest that the results were due to Gluconate, since the same results could not be reproduced when Zn sulfate was used (Ref.)
- 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. (Ref.) This is a very nice case report we previously discussed in the post I wrote on zinc (Ref.), where a patient experienced reduction in hepatic metastases and finally the treatment produced clinical remission of the stage IV metastatic ocular melanoma. The treatment used included Disulfiram and Zn Gluconate. Also here, the authors of the paper above suggest that the patient may have been successfully treated due to the Gluconate element, since the clinical trials including Disulfiram withouth Gluconate did not showed positive results, such as this trial.
