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McCarty et al. J Cancer Metastasis Treat 2020;6:20 I http://dx.doi.org/10.20517/2394-4722.2020.47 Page 3 of 5

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
[27]
line, possibly explaining the clinical toxicity of clioquinol .

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
[28]
high with zinc dipicolinate, as opposed to zinc sulfate . 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
[31]
impact on zinc levels in erythrocytes, hair, and urine . 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
[32]
dipicolinate supplement .
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
[33]
zinc is believed to arise at an early stage of prostate cancer evolution .
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
[34]
to hyperthermia and/or high-dose intravenous ascorbate . 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] .

DECLARATIONS
Authors’ contributions
Conceived and wrote the first draft: McCarty MF
Provided suggestions that were incorporated into the final manuscript: Iloki-Assanga S, Lujan LL