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Page 2 of 5 McCarty et al. J Cancer Metastasis Treat 2020;6:20 I http://dx.doi.org/10.20517/2394-4722.2020.47

VIABILITY OF PROSTATE CANCER MAY REQUIRE EXCLUSION OF ZINC
Prostate epithelium is characterized by high intracellular levels of zinc, particularly within the
[1]
mitochondria . 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
[2,3]
cycle . 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 . This
[4-8]
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-
[14]
deficient human prostate cancer .

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
[10]
PKC . 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 K of about 100 nmol/L [15-18] .
i
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 . In mammary epithelial cells, ZnT2
[24]
transports zinc into mitochondria, and over-expression of this protein lowers cellular ATP levels and
[24]
oxygen consumption, and promotes apoptosis; oxidant production was not measured in this study .
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-