Zinc - Clioquinol

New paper below [1].

Many will know that the normal prostate has the highest concentration of zinc in the body.  Normal prostates also have large amount of citrate, & it seems that the role of zinc is to protect the citrate from being metabolized.

An early event in the development of PCa is a reduction in the number of zinc uptake transporters, specifically ZIP1.  It has been known for 65 years that zinc is depleted in PCa tissue.  Furthermore, depletion isn't merely common - it always occurs - suggesting that the elimination of zinc is essential to progression.

Costello (with Franklin) has been involved in PCa-Zinc research for at least 20 years.  The latest paper provides a comprehensive review of zinc in normal & malignant prostatic tissue, but the full text isn't free.  However, from the Abstract:

"The requirement for decreased zinc resulting from down regulation of ZIP1 to prevent zinc cytotoxicity in the malignant cells is described as an essential early event in prostate oncogenesis. This provides the basis for the concept that an agent (such as the zinc ionophore, clioquinol) that facilitates zinc uptake and accumulation in ZIP1-deficient prostate tumors cells will markedly inhibit tumor growth."

Clioquinol is an antifungal drug [2].

Dou, et al, (2007) [3] looked at Clioquinol because it is a copper chelator:

"The most serious problem associated with many currently used anticancer drugs is their inability to distinguish normal cells from tumor cells. To develop novel selective anticancer agents, it is of paramount importance to explore the distinct properties or features of cancer cells from normal cells. One unique feature of tumors is the elevated levels of copper, which has been found in many types of human cancers, including prostate, breast, colon, lung, and brain ( 17– 21). Accumulated evidence has shown that copper, but not other transition metals, is a cofactor essential for tumor angiogenesis ( 13, 14)."

"... we found that clioquinol could interact with copper and form a new complex that was a proteasome inhibitor, an AR {androgen receptor} suppressor, and an apoptosis {cell death} inducer in cultured human prostate cancer LNCaP and C4-2B cells."

In a paper from last August [4], Costello reveals that zinc/PCa research is not without its frustrations:

"A zinc ionophore (e.g. Clioquinol) treatment to increase malignant zinc levels is a plausible treatment of prostate cancer. However, skepticism within the clinical/biomedical research community impedes significant progress leading to such a zinc treatment."

Some may have heard that zinc can actually promote PCa.  Costello:

"This view arose from an NIH-Harvard collaborative epidemiology report in 2003 [40], in which Leitzmann et al concluded that “we found that excessively high supplemental zinc intake was associated with an increased risk of advanced prostate cancer. “The immediate and continued notoriety given to this report is evident from the widespread pronouncements in various news media and notices from health institutions; such as: Health Day News (July 2, 2003) “Men who overdose on zinc supplements more than double their risk of prostate cancer, a government study finds”; the Washington Post (July 1, 2003), “Study Links Zinc, Prostate Cancer-Men who take too much zinc may be raising their prostate cancer risk, U.S. researchers said yesterday”; the Mayo Clinic Health Letter (May, 2004) “Large doses of zinc may increase risk of prostate cancer.”

"Prior to 2003, the various epidemiology reports had concluded that zinc intake (diet and supplement) either protects against prostate cancer; or promotes prostate cancer; or has no effect on prostate cancer [41,42]. Despite the fact that the Leitzmann report and conclusion had not been corroborated by any other epidemiology studies, and is not supported by the clinical status of zinc in prostate cancer; contemporary clinicians and investigators continue to cite the Leitzmann et al study as evidence that zinc treatment will exacerbate the development and progression of prostate cancer. Most importantly, two recent major epidemiology studies reached the following conclusion: “In this prospective cohort, long-term supplemental zinc intake was associated with reduced risk of clinically relevant advanced disease” [43] and “These results suggest that high dietary intake of zinc is associated with lower prostate cancer-specific mortality affer diagnosis, particularly in men with localized disease” [44]. In addition, we have published rebuttals and reviews [41,42,45,46]. which describe the questionable results and conclusions inherent in the epidemiology study. Particularly important is our extensive review [46] that analyzes in detail the shortcomings of the Leitzmann et al data and conclusions. In addition, others also raised issue with the Leitzmann et al study and conclusions [47,48].

"Relative to the issue of zinc treatment for prostate cancer, the epidemiology conclusions should not be weighed against the overwhelming clinical, physiological, and experimental evidence. If anything, the current assessment of the epidemiology reports would be supportive of a zinc treatment approach for prostate cancer. Unfortunately, we are confronted with the enigma expressed by outstanding epidemiologists [49]. Dr. Trichopoulos who stated that epidemiology studies “studies will inevitably generate false positive and false negative results with disturbing frequency... when people do take us seriously, we may unintentionally do more harm than good” and Dr. Walker who also stated “The first one or two papers about a suspected association spring into the general public consciousness in a way that does not happen in any other field of scientific endeavor. And once a possible link is in the public eye, it can be virtually impossible to discredit”. Affer twelve years of a dominant epidemiological misrepresentation of the zinc relationship in prostate cancer, this dilemma still confronts us."

Cadmium is invariably found where zinc is mined, & cheap zinc supplements may be contaminated.  Krome & Harms raised this point in 2003 [5]:

"All commercially available zinc supplements that we analyzed (2) contained detectable levels of cadmium; however, the amounts varied by almost 40-fold when based on a fixed amount of zinc (e.g., 15 mg, the recommended daily allowance for zinc). We estimate that consumption of approximately 140 mg/day of zinc [the median daily level of zinc supplement intake among the high-intake group studied by Leitzmann et al. (1)] in the zinc supplement that we found contains the highest cadmium-to-zinc ratio would yield a cadmium dose of approximately 19 μg/day."

On the other hand, one should never take high doses of a single mineral, such that the level creates antagonism with other essential minerals.  e.g. zinc & selenium should be kept in balance.

Like many men, I avoided zinc supplements for a while.  Mostly because I figured that in the absence of ZIP1, zinc was irrelevant to PCa.  But a 2008 study [7] convinced me to try zinc citrate.  It involved extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor.  i.e. the zinc acts from outside the cell:

"Our results indicate that extracellular Zn2+ and Zn2+Cit, by triggering or desensitizing ZnR activity, distinctly regulate prostate cancer cell growth. Thus, therapeutic strategies based either on Zn2+ chelation or administration of Zn2+Cit may be effective in attenuating prostate tumor growth."

I chose the latter approach & use 50 mg zinc citrate from a reliable source:

swansonvitamins.com/nutrico...

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/271...

[2] en.wikipedia.org/wiki/Clioq...

[3] cancerres.aacrjournals.org/...

[4] ncbi.nlm.nih.gov/pmc/articl...

[5] jnci.oxfordjournals.org/con...

[6] carcin.oxfordjournals.org/c...

[7] carcin.oxfordjournals.org/c...

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