New paper below [1].
These guys seem upset:
"Efficacious chemotherapy does not exist for treatment or prevention of prostate ... carcinomas ... Zinc treatment offers a potential solution; but its support has been deterred by adverse bias."
The Franklin & Costello partnership goes back at least 40 years & 102 papers. Their first paper was titled: "Citrate uptake and oxidation by fragments of rat ventral prostate."
In 1998, there was: "Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer." [2]
"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 zinc accumulation 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."
In essence, the zinc is present to prevent the citrate from being oxidized & used for cellular energy.
"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."
In 1999 [3]:
"Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone."
"In the present studies the uptake and accumulation of zinc were determined in the human malignant prostate cell lines LNCaP and PC-3. The results demonstrate that LNCaP cells and PC-3 cells possess the unique capability of accumulating high levels of zinc. Zinc accumulation in both cell types is stimulated by physiological concentrations of prolactin and testosterone."
"The studies support the concept that these prostate cells express a unique hormone-responsive, plasma membrane-associated, rapid zinc uptake transporter gene associated with their unique ability to accumulate high zinc levels."
Also in 1999 [4]
"Inhibitory effect of zinc on human prostatic carcinoma cell growth."
"Incubation of the prostate carcinoma cell lines with physiological levels of zinc resulted in the marked inhibition of cell growth."
In 2003 [5]:
"Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells."
"The prostate gland of humans and other animals accumulates a level of zinc that is 3-10 times greater than that found in other tissues. Associated with this ability to accumulate zinc is a rapid zinc uptake process in human prostate cells, which we previously identified as the hZIP1 zinc transporter. We now provide additional evidence that hZIP1 is an important operational transporter that allows for the transport and accumulation of zinc. The studies reveal that hZIP1 ... but not hZIP2 ... is expressed in the zinc-accumulating human prostate cell lines, LNCaP and PC-3."
"Uptake of zinc from zinc chelated with citrate was as rapid as from free zinc ions; however, the cells did not take up zinc chelated with EDTA. The cellular uptake of zinc is not dependent upon an available pool of free Zn(2+) ions. Instead, the mechanism of transport appears to involve the transport of zinc from low molecular weight ligands that exist in circulation as relatively loosely bound complexes with zinc."
In 2005 [6]:
"Zinc and zinc transporters in normal prostate and the pathogenesis of prostate cancer."
"Zinc is an essential metal for all cells. It plays a role in a wide variety of physiological and biochemical processes. In the prostate epithelial cell the accumulation of high cellular zinc is a specialized function that is necessary for these cells to carry out the major physiological functions of production and secretion of citrate. The production of citrate and its secretion into prostatic fluid is a differentiated function of the prostate epithelial cells that is apparently important for reproduction. The loss of citrate and zinc accumulation is the most consistent and persistent characteristic of prostate malignancy. This characteristic of prostate cancer indicates that the lost ability of the malignant cells to accumulate zinc and citrate is an important factor in the development and progression of malignancy. The lost ability of the epithelial cells to accumulate zinc and thus to also accumulate citrate is the result of decreased expression of specific zinc uptake transporters."
"These effects of lost zinc accumulation contribute to the metabolic transformation of normal citrate producing prostate epithelial cells to citrate-oxidizing, energy-efficient prostate cancer cells."
The story so far ...
- citrate is an important part of the ejaculate
- zinc protects citrate from being used for energy
- the ZIP1 zinc transporter facilitates rapid uptake of zinc
- ZIP1 is downregulated in PCa
In 2008 [7]:
"Zinc as an anti-tumor agent in prostate cancer ..."
"In addition to {the} metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc."
"To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer."
In 2012 [8]:
"The search for efficacious anticancer agents is imperative. One potential agent is zinc, which is decreased in the development of some cancers in order to avoid its cytotoxic/tumor suppressor effects on the malignant cells. This provides the basis and opportunity to employ a treatment regimen that restores elevated zinc levels in the malignant cells and elicits the cytotoxic/tumor suppressor effects of zinc. The enigma is that this approach and expectation has not reached fruition. The question is “why?”."
"For prostate cancer, the key issue is to deliver zinc into ZIP1-deficient malignant cells and increase the cellular level of mobile reactive zinc, which will manifest the cytotoxic/tumor suppressor effects of zinc."
"Until recently, we considered that the implications and role of zinc as identified in prostate cancer were highly specific for prostate cancer. However, it is now evident that the zinc relationships and role in prostate cancer is a more ‘general phenomenon’ that is applicable to a variety of cancers; although there exists specific differences and nuances for each specific cancer. This is an important revelation. What is the underlying commonality for this role of zinc in cancer? Should we now consider a consistent implication of zinc as an important event in the carcinogenesis process applicable to many cancers? If so, what is the common oncogenetic event that leads to altered zinc in the transformation of normal cells to malignant cells? Thus, a host of issues and questions now surface regarding the implication of zinc in the development and progression of cancer."
In 2015 [9]:
"Evidence that Human Prostate Cancer is a ZIP1-Deficient Malignancy that could be Effectively Treated with a Zinc Ionophore (Clioquinol) Approach"
"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."
"This report reviews the clinical and experimental background, and presents new experimental data showing Clioquinol suppression of prostate malignancy; which provides strong support for a zinc ionophore treatment for prostate cancer."
In 2016 [10]:
"Zinc Ionophore (Clioquinol) Inhibition of Human ZIP1-Deficient Prostate Tumor Growth in the Mouse Ectopic Xenograft Model: A Zinc Approach for the Efficacious Treatment of Prostate Cancer"
I don't know how old Franklin & Costello are, but they must be getting on - but seemingly, getting nowhere in terms of interesting other researchers.
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/278...
[2] ncbi.nlm.nih.gov/pubmed/960...
[3] jbc.org/content/274/25/1749...
[4] ncbi.nlm.nih.gov/pmc/articl...
[5] ncbi.nlm.nih.gov/pmc/articl...
[6] ncbi.nlm.nih.gov/pmc/articl...
[7] ncbi.nlm.nih.gov/pmc/articl...
[8] ncbi.nlm.nih.gov/pmc/articl...
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