The elements were selenium (Se), zinc (Zn) and copper (Cu).
"In a prospective study, we measured the associations between three serum elements (Se, Zn and Cu) and the prognosis of 1475 patients with four different types of cancer (breast, prostate, lung and larynx) from University Hospitals in Szczecin, Poland. The elements were measured in serum taken after diagnosis and prior to treatment. Patients were followed from the date of diagnosis until death from any cause or until the last follow-up date (mean years of follow-up: 6.0-9.8 years, according to site)."
A Se level in the highest quartile was ... associated with a reduced mortality (HR = 0.66 ...) in all-cause mortality for all cancers combined.
"Zn level in the highest quartile was also associated with reduced mortality (HR = 0.55 ...).
"In contrast, a Cu level in the highest quartile was associated with an increase in mortality (HR = 1.91 ...)"
***
One must be careful when interpreting the selenium finding. Selenium deficiency is common in countries where there is little selenium in the soil. Deficiency is rare in the U.S. & Canada, since wheat is grown is selenium-rich soil. In the UK, deficiency became common on entry into the EU because Britain was forced to switch from Canadian to European wheat.
"In recent years, in a considerable number of Polish inhabitants, the concentration of Se in blood plasma has been relatively low-about 50-55 microg/l, and the calculated daily dietary intake about 30-40 microg/day." (2003) [2]
In the U.S., being in the second decile is sufficient and one should not aim for the fourth quartile IMO. The SELECT trial is evidence that supplementation might be dangerous for those already in the upper deciles.
In the UK, it might be prudent for men with PCa to supplement with the recommended daily intake. Selenium is a mineral where more is not better.
For other countries, Google <"selenium deficiency" country>.
***
A good zinc status has been associated with prostate health, however, an old study by Edward Giovannucci reported an association between high intake and aggressive PCa. (2003) [3]:
"Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29"
This scared away many men, but zinc is protective against cadmium.
Unfortunately, zinc & cadmium are found together and an analysis of zinc supplements found that many contained unacceptable cadmium levels, which might explain the association with advanced disease.
In addition, men who are at high risk for PCa might supplement with high doses, giving the appearance of cause & effect.
Giocannucci had a recent update [4]:
"During a median follow-up of 28.3 years, we documented 6,980 incident prostate cancer cases including 1,053 lethal and 1,143 aggressive. Zinc supplement use was not associated with overall, localized, low- and intermediate-grade prostate cancer.
"However, compared to never-users, men who used supplement zinc more than 75 mg/day were at higher risk for lethal (HR: 1.76 ...) and aggressive prostate cancer (HR: 1.80 ...).
"Similarly, men who took supplemental zinc for 15 or more years had a higher risk for lethal (HR: 1.91 ...) and aggressive prostate cancer (HR: 1.55 ...)."
I have been using 50 mg zinc citrate from NutriCology - they test each batch for cadmium. [5]
***
I see no reason why a man with PCa would take a copper supplement (- or a multi-mineral supplement containing copper.)
I have copper pipes and well water with a low enough pH to cause copper staining. Consequently, I use a water filter and run the tap first thing in the morning.
It is worth noting that zinc can interfere with copper uptake, so I might have some protection.
I have written elsewhere about the importance of a good magnesium:calcium ratio. One benefit is that magnesium increases fecal copper, whereas as calcium decreases it.
Here is a similar paper from Saudi researchers from 2019-20. The abstract is copied below and a screen shot of the control vs PCa patients is attached to the reply.
Serum Levels of Selenium, Zinc, Copper, Manganese, and Iron in Prostate Cancer Patients, Current Urology, Original Paper, Received: February 02, 2019, Accepted: February 26, 2019, Published online: March 20, 2020.
Variations of trace element contents may be associated with several diseases including metabolic disorders, cellular growth disturbance, mutation and tumorigenesis. Prostate cancer is the second most common male cancer worldwide and stand fifth most common male cancer in Saudi Arabia.
Objective:
In the present study, Serum levels of selenium, zinc, copper, manganese, and iron were measured in patients with BPH and prostate cancer aiming to explore the association between these elements and prostate cancer.
Patients and Methods:
The study included 40 newly diagnosed prostate cancer patients, 22 patients with BPH and 30 healthy male subjects. All participant groups had similar socio-economic levels. Fasting blood samples were collected from all subjects and before any intervention for the patients. Serum PSA concentrations were analyzed by ELIZA and trace elements Se, Zn, Cu, Mn and Fe were measured by ICP-MS.
Results:
Serum Se, Zn, and Mn levels of prostate cancer patients were significantly decreased compared to control groups. The levels of serum Cu and Fe were significantly higher in prostate cancer patients than in control groups.
Conclusion:
In the present study, an association was noticed between serum trace elements disturbance and prostate cancer. The decreased levels of Se, Zn, and Mn, and increased Cu and Fe levels may play significant roles in the initiation of prostate cancer. However, future prospective studies on the causes of trace elements alteration in prostate cancer patients are needed as well as to illustrate the relation between different prostate cancer stages and trace elements concentrations.
* * *
I did a bit of research on Cu and PCa earlier this year and had started a post that never got finished. I'm headed out to the Y, but will take a look at that effort when I get back.
Thanks, as always, for continually turning over the seemingly endless metabolic/medical stones that relate to our common disease.
To focus just on Cu, when for whatever reason (that I can't now remember) I started looking into research on Cu and cancer, this article was the one that initially got my interest up. Here is Part One of some of the research I found linking PCa & Cu.
Exploiting Cancer’s Proclivity for Copper to Treat Prostate Cancer, Duke Health, Oncology, Urology, by Catherine Lewis, Published August 1, 2017
In July 2017, Duke investigators began enrolling patients in a phase 1 clinical trial (NCT02963051) to test the safety of a novel therapy for prostate cancer based on the proclivity of prostate cancer cells for copper.
The therapy was developed after a 2014 preclinical study by Duke researchers showed that, when the compound disulfiram is coadministered with copper, the drug can specifically target prostate tumor cells in castrate-resistant models of the disease.
Although many studies have shown that tumor cells have increased copper intake, the Duke study uncovered a unique approach to treatment, says Duke medical oncologist Daniel George, MD, who was involved in the preclinical study and is a co-investigator on the clinical trial.
“We first tried to limit copper in prostate tumor cells. But the doses of chelating agent we had to use to get the copper levels low enough would have been too toxic for patients,” he says. “So we turned the concept on its head: Feed the tumor copper—give it all the copper it wants—and then screen for drugs that kill cancer cells when they’re loaded with copper.”
The screen revealed that disulfiram, which can kill tumor cells on its own, is much more effective when tumor cells are loaded with copper. Particularly exciting, George says, was that the treatment also targeted hormone-resistant prostate cancer cells.
“What has us excited is that this is something we can use when all our hormonal therapies have failed,” George says. “Rather than trying to shut down the hormone receptor, we can use it to increase copper uptake in the tumor.”
In addition to testing the new treatment strategy on traditional patients whose disease has failed standard hormonal therapies or chemotherapies and have bone-dominant disease, the new clinical trial includes 2 other cohorts: those with visceral disease and those with neuroendocrine prostate cancer.
The treatment may be effective against visceral disease, George says, because disulfiram is likely absorbed at high concentrations in the gut and liver. Patients with neuroendocrine prostate cancer may also see benefit, because neuroendocrine prostate cancer responds to platinum-based treatment, a therapeutic strategy that exploits the copper transporter.
George notes that the trial is not only novel in its treatment strategy but also in its funding sources. Rather than being supported by an industry partner, the trial is funded by crowdsourcing. One such charity is Give 1 for Dad, which was created by the son of a man with prostate cancer. Additional funding is being provided by a grant awarded to Tian Zhang, MD, a junior faculty member in George’s group. Any treatments developed as a result will therefore be generic and potentially more affordable.
Also exciting, he says, is that, because other cancer cell types also uptake high copper levels, if the treatment strategy works, then it could be modified to treat other types of cancer such as melanoma and breast cancer.
The link to the clinical trial (that was ended early due to no evidence of eficacy) is here:
A Phase Ib Study of Intravenous Copper Loading With Oral Disulfiram in Metastatic, Castration Resistant Prostate Cancer, Recruitment Status : Terminated (Study stopped due to lack of efficacy.), First Posted : November 15, 2016, Last Update Posted : September 16, 2021
So after an auspicous start with broad cancer treatment potential, it seems the concept failed to provide any benefit.
Here is an in-depth mouse study from the same time period that looks at using copper-ionophores to alter intercellular Cu distribution
Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution, Oncotarget, 2016 Jun 14; 7(24): 37064–37080. Published online 2016 May 9.
And a more recent Frontiers In Molecular Biosciences paper that evaluated the therapeutic potential of Copper-64 Chloride for treatment on multiple PCa cancer cells. The following is the study introduction (full access):
Prostate cancer (PCa) is the second most common cancer type in men, and in advanced metastatic stages is considerable incurable. This justifies the need for efficient early diagnostic methods and novel therapies, particularly radiopharmaceuticals with the potential for simultaneous diagnosis and therapy (theranostics). We have previously demonstrated, using monolayer-cultured cells, that copper-64 chloride, a promising theranostic agent for PCa, has the potential to induce significant damage in cancer cells while having minimal side effects in healthy tissues. Here, we further explored this compound for its theranostic applications using more advanced PCa cellular models, specifically multicellular spheroids. Namely, we evaluated the cellular uptake of 64CuCl2 in three human PCa spheroids (derived from 22RV1, DU145, and LNCaP cells), and characterized the growth profile and viability of those spheroids as well as the clonogenic capacity of spheroid-derived cells after exposure to 64CuCl2.
Furthermore, the populations of cancer stem cells (CSCs), known to be important for cancer resistance and recurrence, present in the spheroid models were also evaluated using two different markers (CD44 and CD117). 64CuCl2 was found to have significant detrimental effects in spheroids and spheroid-derived cells, being able to reduce their growth and impair the viability and reproductive ability of spheroids from both castration-resistant (22RV1 and DU145) and hormone-naïve PCa (LNCaP). Interestingly, resistance to 64CuCl2 treatment seemed to be related with the presence of a CSC population, since the most resistant spheroids, derived from the DU145 cell line, had the highest initial percentage of CSCs among the three cell lines under study. Altogether, these results clearly highlight the theranostic potential of 64CuCl2.
Copper-64 Chloride Exhibits Therapeutic Potential in Three-Dimensional Cellular Models of Prostate Cancer, Frontiers In Molecular Biosciences, Original Research article, 01 December 2020.
Wilson's Disease is a genetic disorder in which dangerous levels of copper accumulate.
"Wilson's disease is typically treated with dietary changes and medication. Dietary changes involve eating a low-copper diet and not using copper cookware. Medications used include chelating agents, such as trientine and d-penicillamine, and zinc supplements." [1]
I had hoped that a treatment for Wilson's would be useful for PCa, but such hopes were dashed in 2006 [2]:
This Phase II trial used the copper-chelating agent tetrathiomolybdate (TM):
"Bis-choline tetrathiomolybdate has been evaluated in clinical trials in patients with various forms of cancer and has received orphan designation in the US and EU as a potential therapy against Wilson's disease." [3]
(The rationale for targeting copper, is that it is essential for angiogenesis.)
"Results: Seventeen of 19 patients achieved copper deficiency on TM therapy. Of the 16 evaluable patients, 14 developed progressive disease, 1 discontinued therapy because of toxicity and 1 patient opted to discontinue therapy because of rising prostate-specific antigen level without objective evidence of progressive disease. Levels of vascular endothelial growth factor, IL-6 and IL-8, but not basic fibroblast growth factor, were elevated when compared to normal controls prior to TM therapy, but there was no significant change during therapy. There was no correlation between prostate-specific antigen and levels of angiogenesis factors.
"Conclusions: Copper depletion with TM did not delay disease progression in patients with asymptomatic metastatic HRPC."
***
Interestingly, copper depletion drugs have been used in other PCa studies for different reasons. e.g. (2016) [4]:
"Polyamine metabolism is an attractive anticancer drug target, since polyamines are absolutely required for cellular proliferation, and increased levels of polyamines and their biosynthetic enzyme ornithine decarboxylase (ODC) are associated with cancer.
"Triethylenetetramine (TETA) is a charge-deficient isosteric analogue of the polyamine spermidine (Spd) and a Cu(II)-chelating compound used for the treatment of Wilson's disease, and it has been implicated as a potential anticancer therapeutic drug.
"In the present study, we studied the effects of TETA in comparison with two other Cu(II)-chelators, D-penicillamine (PA) and tetrathiomolybdate (TTM), on polyamine metabolism in DU145 prostate carcinoma, MCF-7 breast carcinoma and JEG-3 choriocarcinoma cells.
TETA induced antizyme, down-regulated ODC and inhibited [(14)C] Spd uptake. Moreover, it completely prevented α-difluoromethylornithine (DFMO)-induced increase in [(14)C] Spd uptake, and inhibited [(14)C] putrescine (Put) uptake and ODC activity in vivo Seven-day treatment of DU145 cells with TETA caused growth cessation by reducing intracellular polyamine levels and suppressing the formation of hypusinated eukaryotic translation initiation factor 5A (eIF5A). TETA or its N-acetylated metabolites also inhibited spermine (Spm), diamine and semicarbazide-sensitive amine oxidases and decreased the level of intracellular reactive oxygen species. Moreover, TETA inhibited the utilization of Put as energy source via the tricarboxylic acid (TCA) cycle, as indicated by decreased production of (14)CO2 from [(14)C] Put.
"These results indicate that TETA attacks multiple proven anticancer drug targets not attributed to copper chelation, which warrants further studies to reveal its potential in cancer chemoprevention and cure."
Post Response Part 2-A to Patrick (pca2004 et al). (Parts 2-B & 2-C to follow.) These additional research papers look at various aspects of Cu and PCa, both from a diagnostic point of view as well as possible avenues for treatment. I've added a Part 2-B due to HU reply length limit and Part 2-C to discuss the levels of Cu in various foods and personal speculations on methods to control Cu levels - or whether that is even realistically possible or desirable from an overall health point of view. But first to the additional research . . .
Here is a basic research paper (for any remaining Chemists in our readership) about the development of 18 newly derived Cu(I) complexes and their cytoxic effectiveness in various PCa cell lines. Nothing here is readily actionable without your own chemistry set and a very deep knowledge of biochemistry.
New copper(I) complexes selective for PCa cells, Dalton Transactions, Royal Society of Chemistry, 2020.
From the introduction:
Despite the clinical success of platinum-based drugs (Cisplatin, Carboplatin and Oxaliplatin) that have been widely used in cancer treatment, they present keen limitations in their use mainly due to the poor selectivity towards cancer cells leading to the occurrence of severe side effects and to increasing reports of drug resistance cases. For this reason, there is still an urgent need for the development of new drugs with improved pharmacological properties. In the search of new compounds, one strategy involves the use of bio-essential metals, as they are expected to be less toxic because the human organism has already well-defined metabolic pathways for these metals. Among them, copper has been attracting special attention.
. . . The most cytotoxic compound, [Cu(dppe)(2-ap)][BF4] (16), where dppe = 1,2-bis(diphenylphosphano) ethane and 2-ap = 2-acetylpyridine, showed high level of cellular internalization, generation of intracellular ROS and activation of cell death mechanism viaapoptosis/necrosis. Owing to its high cytotoxic activity for LNCap cells, which was 70-fold increases when compared to normal prostate cells (RWPE), complex (16) was found to be the most promising for further research in prostate cancer.
New copper(I) complexes selective for PCa cells, Dalton Transactions, Royal Society of Chemistry,Published on 04 August 2020. Downloaded on 8/5/2020 2:09:33 AM.
This study from China looks at the ability of several steroid-based compounds to inhibit the cellular uptake of Cu in PCa. Once agian, while nothing here is really actionable without your own chemistry set, it does offer insights into possible avenues for Cu reduction to control/reduce PCa proliferation and growth.
Reduction in Copper Uptake & Inhibition of Prostate Cancer Cell Proliferation by Novel Steroid-based Compounds, Anticancer Research, December 2021.
Abstract
Background/Aim: Knockdown of human copper transporter 1 has been associated with reduction in copper uptake and suppression of prostate cancer cell proliferation and tumor growth. This study evaluated the effects of steroid-based compounds on copper uptake and proliferation of prostate cancer cells based on their anticancer activity and previous docking analysis of steroid-based copper transporter 1 inhibitors. Materials and Methods: We synthesized several new steroid-based compounds and used 64Cu uptake assay and copper quantification assay with inductively coupled plasma mass spectrometry to study their effects on the cellular copper uptake by prostate cancer cells. Additionally, we used CCK-8 cell proliferation assay to study their effects on the proliferation of prostate cancer cells. Results: Significant reduction in cellular copper uptake was observed in the prostate cancer cells treated with these new steroid-based compounds. Moreover, proliferation of prostate cancer cells was suppressed by treatment with the steroid-based compound 6, which had the strongest copper uptake inhibition activity. Conclusion: Reduction in copper uptake and inhibition of cell proliferation were demonstrated in prostate cancer cells treated with the new steroid-based compounds synthesized in this study. Steroid-based copper transporter 1 inhibitors may become novel anticancer drugs for targeted anti-copper therapy of prostate cancer and other copper hypermetabolic cancers.
* * *
Reduction in Copper Uptake & Inhibition of Prostate Cancer Cell Proliferation by Novel Steroid-based Compounds, Anticancer Research, December 2021, 41 (12) 5953-5958
And finally, here is a study that looks at the utility of various amino acids in cellular Cu uptake by PCa cell types. (I especially like that they used Hank's Balanced Salt Solution for the 64 Cu measurement. Hank must have once been some sort of salt water fisherman or sea captain, either of which would give him special credence and make him my kind of guy. 😀) It also seems to indicates the need for caution for anyone supplementing with NAC. From the paper's introduction:
L-Cysteine-mediated modulation of copper trafficking in prostate cancer cells: an in vitro and in vivo investigation with 64 Cu and 64 Cu-PET, Metallomics, Royal Society of Chemistry, 2020.
. . .
Copper imbalance is implicated in many diseases, including cancer. Copper in blood is mainly transported by carrier proteins but a small fraction is bound to low molecular weight species, possibly amino acids. Their roles in cellular copper delivery are unknown. Our aim was to test whether accumulation of 64 Cu into cancer-derived cells can be influenced by copper-binding serum amino acids. In vitro cellular accumulation of 64Cu was measured in Hank’s Balanced Salt Solution in the presence of 100 mM L-histidine, L-methionine, L-cysteine and L-threonine. L-Cysteine markedly increased 64 Cu accumulation and retention in DU145, PC3 and SK-OV-3 cells, while some other cell lines did not show an effect. This effect was not due to 64 Cu delivery in the form of a 64 Cu–cysteine complex, nor to reduction of 64 Cu(II) to 64 Cu(I) by L-cysteine. Pre-incubation of cells with L-cysteine increased 64 Cu accumulation, even if L-cysteine was removed from HBSS before 64 Cu was added. The effect of L-cysteine on 64 Cu accumulation was not mediated by increased glutathione synthesis. Despite the demonstrable in vitro effect, pre-injection of L-cysteine precursor N-acetyl-cysteine (NAC) in vivo did not enhance 64 Cu delivery to DU145 xenografts in mice. Instead, it decreased 64 Cu accumulation in the DU145 tumour and in brain, as assessed by PET imaging. We conclude that 64 Cu is not delivered to DU145 cancer cells in vitro as a complex with amino acids but its cellular accumulation is enhanced by L-cysteine or NAC influx to cells. The latter effect was not demonstrable in vivo in the DU145 xenograft.
Significance to metallomics
Copper is an essential element required by all cells. Its metabolism is dysregulated in many diseases. Cancer cells, especially in prostate cancer, typically accumulate more copper than normal cells. In this work we explored how copper is delivered to and retained in cancer cells. We demonstrate that L -cysteine and N-acetyl-cysteine supplementation increases cellular copper retention in prostate cancer cells and in some other cell lines but amino acids in serum are not required to deliver copper ions to transporters for import into the cells tested.
L-Cysteine-mediated modulation of copper trafficking in prostate cancer cells: an in vitro and in vivo investigation with 64 Cu and 64 Cu-PET, Metallomics, Royal Society of Chemistry, Volume 12, Number 10, October 2020, Pages 1451–1618
That's one of the issues/problems with multi-vitamins - as they potentially add to what you are getting in your diet. For some vitamins and minerals that maybe fine, but for others, too much can actually be harmful. I'll post the Part 2-C to my reply to Patrick (I don't yet know what his active status @ FPC is?) when I get time to finish it, That part deals with food sources and how much copper we can get in otherwise very healthy foods. A true dietary delimea of sorts. Check back tomorrow evening and I should be able to get it posted here.
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