A Proposed Treatment With Clioquinol And Cabergoline For The Treatment Of Terminal Prostate Cancer

Joined
Dec 18, 2018
Messages
2,207

J Clin Res Oncol. Author manuscript; available in PMC 2019 Feb 27.
Published in final edited form as:
J Clin Res Oncol. 2019; 2(1): https://asclepiusopen.com/journal-of-clinical-research-in-oncology/volume-2-issue-1/1.pdf.
PMCID: PMC6392423
NIHMSID: NIHMS1007032
PMID: 30828702
A Proposed Efficacious Treatment with Clioquinol (Zinc Ionophore) and Cabergoline (Prolactin Dopamine Agonist) for the Treatment of Terminal Androgen-independent Prostate Cancer. Why and How?
Leslie C. Costello and Renty B. Franklin
Author information Copyright and License information Disclaimer
See other articles in PMC that cite the published article.
Go to:
Abstract
All cases of prostate cancer exhibit the hallmark condition of marked decrease in zinc in malignancy compared to the high zinc levels in the normal and benign prostate. There exists no reported corroborated case of prostate cancer in which malignancy exhibits the high zinc levels that exist in the normal prostate acinar epithelium. The decrease in zinc is achieved by the downregulation of ZIP1 zinc transporter, which prevents the uptake and accumulation of cytotoxic zinc levels. Thus, prostate cancer is a “ZIP1-deficient” malignancy. Testosterone and prolactin are the major hormones that similarly regulate the growth, proliferation, metabolism, and functional activities of the acinar epithelial cells in the peripheral zone (the site of development and progression of malignancy). Testosterone regulation provides the basis for androgen ablation treatment of advanced prostate cancer, which leads to the development of terminal androgen-independent malignancy. Androgen-independent malignancy progresses under the influence of prolactin. These relationships provide the basis for the prevention and treatment of advanced prostate cancer. Clioquinol (zinc ionophore; 5-chloro-7-iodoquinolin-8-ol) is employed to facilitate zinc transport and accumulation in the ZIP1-deficient malignant cells and induce cytotoxic effects. Cabergoline (dopamine agonist) is employed to decrease prolactin production and its role in the progression of androgen-independent malignancy. We propose a clioquinol/cabergoline treatment regimen that will be efficacious for aborting terminal advanced prostate cancer. FDA policies permit this treatment regimen to be employed for these patients.

Keywords: Androgen-independent prostate cancer, cabergoline bromocriptine agonist, clioquinol zinc ionophore, testosterone and prolactin
Go to:
INTRODUCTION
About 165,000 cases of prostate cancer and 30,000 deaths will occur in 2018 in the USA. For advanced prostate cancer, the 5-year survival rate is 30%.[1] The latter includes terminal androgen-independent malignancy (castration-resistant prostate cancer) that results from androgen ablation. Androgen independent cancer remains untreatable despite decades of research to develop a treatment to abort this malignancy. In this review, we will present the background for the development and progression of prostate malignancy, the role of testosterone and prolactin, and the basis for a proposed efficacious treatment that will abort the development and progression of terminal androgen-independent prostate cancer.

Go to:
THE ORGANIZATION OF THE PROSTATE GLAND AND THE INITIATION AND DEVELOPMENT OF PROSTATE MALIGNANCY
The human prostate gland is a complex organ comprised different ontological and analogical regions. The structure of the normal prostate gland includes the peripheral zone (~75%), the central zone (~20%), and the transition zone/periurethral region (~5%). The peripheral zone is the major region where ~90% of malignancy is initiated and progresses. About 10% of malignancy develops in the transition zone but is a more indolent malignancy. The transition zone is the region where benign prostatic hyperplasia develops and then invades the central zone.[2]

These relationships must be recognized in describing functional relationships of the normal prostate gland and the implications in prostate pathology. Unfortunately, many (and likely most) reported physiological and pathophysiological reports do not recognize or identify these relationships and lead to inappropriate and misrepresented conclusions.

Go to:
THE STATUS AND ROLE OF ZINC AND ZIP1 ZINC TRANSPORTER IN PROSTATE CANCER
In seventeen reported population studies,[3] collectively totally several hundred normal prostate versus prostate cancer cases, the zinc levels were decreased in all cases and stages of prostate cancer by 68% ± 3% standard error (P < 0.0001) as compared to normal and benign prostate. Figure 1 shows the high zinc level in the normal acinar epithelial cells, and the loss of zinc in the malignant cells. No corroborated case of prostate cancer exists in which the malignancy exhibits the higher zinc that exists in the normal acinar cells. “Why?”

Figure 1:
Zinc and ZIP1 transporter in normal acinar cells and malignant cells. (a) Black dithizone stain shows high zinc level in normal acinar epithelium and decreased zinc in malignant cells, (b) arrows show localized ZIP1 at the plasma membrane of the normal acinar cells and the absence of ZIP1 in the malignant cells

The high zinc level that exists in the normal peripheral zone acinar epithelial cells (the origin and development of malignancy) is cytotoxic in the malignant cells. Therefore, the malignant cell evolved with mechanisms that prevent the accumulation of the higher zinc levels that exist in the normal cells. A major factor is the downregulation of ZIP1 (Slc39A1) transporter that is responsible for the uptake and accumulation of zinc in the normal cells [Figure 1]. The ZIP1 downregulation and decreased zinc occurs in the development of malignancy and persists throughout the progression of the malignancy, leading to advanced prostate cancer.[4,5] Thus, prostate cancer is a “ZIP1-deficient” malignancy.

Go to:
THE STATUS OF CITRATE IN NORMAL AND MALIGNANT PROSTATE PERIPHERAL ZONE
In addition to being zinc-accumulating cells, the acinar cells of the peripheral zone are also citrate-producing cells, due to zinc inhibition of m-aconitase activity and citrate oxidation through the Krebs cycle. In malignancy, the decreased zinc inhibition of citrate production is removed, and the malignant cells exhibit major decreased citrate.

This is the basis for in situ magnetic resonance spectroscopy imaging (MRSI) for the identification of normal and malignant loci in the peripheral zone [Figure 2].[6]

Figure 2:
In situ magnetic resonance spectroscopy image shows high citrate in normal peripheral zone and marked decreased citrate in malignant loci

Go to:
THE “GENETIC/METABOLIC TRANSFORMATION” IN THE DEVELOPMENT OF PROSTATE MALIGNANCY
It becomes apparent that the metabolism of the normal acinar epithelial cells undergoes “genetic/metabolic transformation” during the development of malignancy. The zinc-related metabolic pathway of citrate metabolism is represented in Figures 3 and and44[5] and reveals that the ZIP1 downregulation/decreased zinc is a genetic/metabolic transformation that occurs in premalignancy and progresses in the development of malignancy. Thus, we characterize prostate cancer as a ZIP1-deficient malignancy. This is an important relationship that should be represented in prostate biomedical research and clinical studies.

Figure 3:
The citrate-related metabolic pathways in malignant and normal prostate epithelial cells

Figure 4:
The genetic/metabolic transformation during the development of prostate malignancy

Go to:
THE STATUS OF ZINC IN EXTRACELLULAR AND INTRACELLULAR FLUIDS
It must be recognized that zinc exists in extracellular and intracellular fluids as either mildly bound to ligands or as tightly bound to ligands, i.e., “Zn ligands.”[7] The former includes exchangeable (“mobile”) reactive Zn ligands such as Zn amino acids and Zn metallothioneins, and the latter includes most Zn proteins/Zn enzymes. The concentration of free Zn++ ion is in the fM-nM range, which is physiologically irrelevant. The mobile reactive Zn ligands have zinc-binding formation constants of logKf=~11 or lower. Zn ligands with logKf~12 and greater are tightly bound, non-exchangeable zinc compounds. In addition, Figure 5 shows that the effects of zinc are dependent on the total zinc concentration of the mobile Zn ligands and not on the free Zn++ ion concentration.

Figure 5:
The effect of zinc concentrations of mobile Zn ligands on the cellular uptake of zinc in prostate PC-3 cells

Go to:
EXPERIMENTAL EVIDENCE FOR ZINC IONOPHORE (CLIOQUINOL) EFFICACIOUS TREATMENT OF ADVANCED PROSTATE CANCER
The relationship of high zinc levels being cytotoxic in prostate malignancy provides a basis for zinc treatment regimen for prostate cancer. The ZIP1-deficient status of prostate malignancy dictates that a process and/or agent is required to deliver zinc from plasma into the ZIP1-deficient malignant cells and manifest the cytotoxic effects of zinc.

One such agent is an ionophore, which will bind zinc to provide a Zn ionophore ligand to facilitate the transport of zinc across the plasma membrane and into the cell. The ionophore must be capable of binding zinc in plasma, thus forming a Zn ionophore ligand. The binding affinity must result in a mobile. Zn ionophore ligand, which is delivered to the malignant site, and facilitates the transport of zinc into the cell. Within the cell, the mobile Zn ionophore will provide the exchangeable Zn that will then exhibit the cytotoxic effects of the increased concentration of zinc. Consequently, this is a complex process that is required for a zinc ionophore to be an efficacious regimen for the treatment of prostate malignancy.

The above zinc ionophore requirements are exhibited by clioquinol, which has a logKf~7–8.[8,9] We achieved successful results with clioquinol treatment of xenograft mice implanted with human ZIP1-deficient PC3 cells that we developed.[10] Subcutaneous administration of clioquinol resulted in ~85% suppression of the ZIP1-deficient tumor growth [Figure 6].

Figure 6:
The effects of the clioquinol treatment of mice with xenograft human ZIP1-deficient tumors. (a) Results of two experiments showing the tumor suppression effects of clioquinol treatment, (b) shows the marked decrease in tumor size in treated mice

Go to:
TESTOSTERONE AND PROLACTIN DUAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF ADVANCED PROSTATE CANCER
It is well established and recognized that testosterone is a major hormone for the regulation of growth, proliferation, metabolism, and functional activities of peripheral zone acinar epithelial cells.[11] Testosterone regulation is through androgen receptor pathway [Figure 7].

Figure 7:
The pathway of testosterone regulation of metabolic genes as represented by mAAT. Testosterone (T); dihydrotestosterone (DHT); androgen receptor (AR); (3) androgen response elements (ARE 1 and 2); basal transcription complex (BTC); mito aspartate aminotransferase (mAAT)

In contrast, the important role of prolactin in males has been largely ignored and/or misrepresented by contemporary investigators and clinicians. Most reported studies (such as[12]) relate to the well-known growth promoting and differentiation effects (cytokine effects) of prolactin, which are mediated predominantly through the tyrosine kinase-associated pathway.

In contrast, prolactin regulation of the metabolic genes in prostate cells is mediated through the direct hormone receptor activation of the phospholipase-diacylglycerol pathway, leading to the direct activation of PKC [Figure 8].[13] This metabolic relationship is the major function of prolactin in the human and animal prostate glands.

Figure 8:
Protein kinase C pathway for prolactin regulation of metabolic gene expression in prostate epithelial cells as represented by mitochondrial aspartate aminotransferase. Prolactin receptor complex (PRL-R); phospholipase C (PLC); diacylglycerol (DG); inositol triphosphate (IP3); protein kinase C (PKC); transcription factor (TF); TPA response element (TRE)

It is important to note that prolactin regulation occurs specifically in the acinar epithelial cells of the posterior peripheral zone, whereas testosterone regulates these and other cells in the prostate gland. Nevertheless, both hormones are involved in the development and progression of advanced prostate cancer. This relationship must be considered in relation to the development and progression of advanced prostate cancer and in the application of treatment regimens for prostate cancer.

Go to:
A PROPOSED REGIMEN THAT INCLUDES CLIOQUINOL TREATMENT AND CABERGOLINE TREATMENT (PROLACTIN DOPAMINE AGONIST) FOR TERMINAL ANDROGEN-INDEPENDENT PROSTATE CANCER
We propose to employ the topical cutaneous application of 3% clioquinol cream to deliver zinc from plasma to the malignant site and into the ZIP1-deficient cells to manifest its cytotoxic effects. The topical cutaneous application of 3% clioquinol cream (also with 1% hydrocortisone) is employed for the treatment of bacterial and fungal skin infections and exhibits little or no adverse local or systemic effects so that the benefit/risk consideration favors its treatment for terminal prostate cancer.

The effective transdermal absorption of clioquinol into plasma and delivery to other tissue sites is evident from its increase in protein-bound iodine and the recovery of clioquinol glucuronide in urine.[14,15] Thus, it is plausible to expect that sufficient Zn clioquinol in circulation will be delivered to primary site prostate malignancy and to metastatic sites, thereby resulting in zinc transport into the ZIP1-deficient malignant cells and manifesting zinc cytotoxicity and abortion of malignancy. This is well supported by the tumor suppression effects of subcutaneous clioquinol treatment in mice [Figure 3].

Its typical treatment protocol for skin disorders is to apply a thin layer of the medication to the affected area and gently rub in, up to 3–4 times daily. For advanced prostate cancer, the cream could be initially applied to ~2 inch area of skin, perhaps once a day. If no adverse side effects become apparent, the treatment might be increased.

The presence of prolactin receptors and prolactin dependency in prostate cancer[1620] dictates that treatment to decrease its production and plasma level is advisable. To achieve this, we propose that cabergoline (dopamine agonist; Dostinex) to decrease the plasma level of prolactin be employed in combination with clioquinol. It has been shown to be more effective than bromocriptine for decreasing the production and plasma level of prolactin and with less adverse side effects.[2123] The treatment should be in accord with the recommended dosage for Dostinex (Dostinex Tablets (cabergoline tablets).).

The possible adverse effects and the efficacy of the combined testosterone and prolactin ablation treatment should be monitored by the levels of PSA, plasma testosterone, and prolactin and imaging of malignancy (e.g., PSMA PET and MRSI).

Go to:
THE FDA “COMPASSIONATE USE” (EXPANDED ACCESS) POLICY: APPLIED FOR THE CLIOQUINOL TREATMENT OF TERMINAL CANCERS
FDA “Expanded access” policy for the use of investigational drugs outside the clinical trial setting for treatment purposes described as: “Patient has a serious disease or condition, or whose life is immediately threatened by their disease or condition; there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; patient enrollment in a clinical trial is not possible; potential patient benefit justifies the potential risks of treatment; providing the investigational medical product will not interfere with investigational trials that could support a medical product’s development or marketing approval for the treatment indication.” (Expanded Access). In addition, the “right to try” legislation provides terminally ill patients an option to try an experimental drug that has met FDA requirement of being a safe drug for human use but need not been shown to be therapeutically effective. This permits the terminally ill patients, who have exhausted all FDA-approved treatments, to proceed with an experimental treatment that could eliminate or improve their terminal condition. Also, the FDA “off-label use” and “right to try” policies should be employed for the combined 3% clioquinol cream and cabergoline treatment regimen for the treatment of terminal prostate cancer patients with androgen-independent prostate cancer.

Go to:
CONCLUSIONS
Terminal androgen-independent prostate is prolactin dependent, decreased zinc, ZIP1- deficient malignancy in which conditions that will increase zinc uptake and accumulation will exhibit cytotoxic/tumor suppressor effects.

Experimental studies demonstrate that the topical cutaneous application of 3% clioquinol cream will provide transdermal absorption of clioquinol into blood, which will result in mobile ZnCQ that is delivered to malignant sites, transports zinc into the ZIP-deficient malignant cells, and induces cytotoxic/tumor suppression effects. Treatment with the dopamine agonist, cabergoline, will decrease plasma prolactin level, thereby preventing prolactin-induced progression of androgen-independent malignancy.

FDA “Compassionate use” policies should permit clioquinol and cabergoline treatment of terminal androgen-independent cancer and without unnecessary delay.

Go to:
ACKNOWLEDGMENT
Studies of LC Costello and RB Franklin cited herein were supported by NIH grants CA79903, DK076783, and DK42839.

Go to:
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. [PubMed] [Google Scholar]
2. Timms BG, Mohs TJ, Didio LJ. Ductal budding and branching patterns in the developing prostate. J Urol 1994;151:1427–32. [PubMed] [Google Scholar]
3. Zaichick VYe Sviridova TV, Zaichick SV. Zinc in the human prostate gland: Normal, hyperplastic and cancerous. Int Urol Nephrol 1997;29:565–74. [PubMed] [Google Scholar]
4. Franklin RB, Feng P, Milon B, Desouki MM, Singh KK, Kajdacsy-Balla A, et al. HZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol Cancer 2005;4:32. [PMC free article] [PubMed] [Google Scholar]
5. Costello LC, Franklin RB. A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. Arch Biochem Biophys 2016;611:100–12. [PMC free article] [PubMed] [Google Scholar]
6. Costello LC, Franklin RB, Narayan P. Citrate in the diagnosis of prostate cancer. Prostate 1999;38:237–45. [PMC free article] [PubMed] [Google Scholar]
7. Costello LC, Fenselau CC, Franklin RB. Evidence for operation of the direct zinc ligand exchange mechanism for trafficking, transport, and reactivity of zinc in mammalian cells. J Inorg Biochem 2011;105:589–99. [PMC free article] [PubMed] [Google Scholar]
8. Ferrada E, Arancibia V, Loeb B, Norambuena E, Olea-Azar C, Huidobro-Toro JP, et al. Stoichiometry and conditional stability constants of Cu(II) or Zn(II) clioquinol complexes; implications for Alzheimer’s and Huntington’s disease therapy. Neurotoxicology 2007;28:445–9. [PubMed] [Google Scholar]
9. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 2001;30:665–76. [PubMed] [Google Scholar]
10. Costello LC, Franklin RB, Zou J, Naslund MJ. Evidence that human prostate cancer is a ZIP1-deficient malignancy that could be effectively treated with a zinc ionophore (Clioquinol) approach. Chemotherapy (Los Angel) 2015;4:152. [PMC free article] [PubMed] [Google Scholar]
11. Costello LC, Franklin RB. Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm Metab Res 2002;34:417–24. [PMC free article] [PubMed] [Google Scholar]
12. Goffin V Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge. Pharmacol Ther 2017;179:111–26. [PubMed] [Google Scholar]
13. Costello LC, Franklin RB. Effect of prolactin on the prostate. Prostate 1994;24:162–6. [PubMed] [Google Scholar]
14. Fischer T, Fagerlund C, Hartvig P. Absorption of 8-hydroxyquinolines through the human skin. Acta Derm Venereol 1978;58:407–11. [PubMed] [Google Scholar]
15. Stohs SJ, Ezzedeen FW, Anderson AK, Baldwin JN, Makoid MC. Percutaneous absorption of iodochlorhydroxyquin in humans. J Invest Dermatol 1984;82:195–8. [PubMed] [Google Scholar]
16. Kadar T, Ben-David M, Pontes JE, Fekete M, Schally AV. Prolactin and luteinizing hormone-releasing hormone receptors in human benign prostatic hyperplasia and prostate cancer. Prostate 1988;12:299–307. [PubMed] [Google Scholar]
17. Verhelst J, Abs R, Maiter D, van den Bruel A, Vandeweghe M, Velkeniers B, et al. Cabergoline in the treatment of hyperprolactinemia: A study in 455 patients. J Clin Endocrinol Metab 1999;84:2518–22. [PubMed] [Google Scholar]
18. Colao A, Di Sarno A, Landi ML, Scavuzzo F, Cappabianca P, Pivonello R, et al. Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: A prospective study in 110 patients. J Clin Endocrinol Metab 2000;85:2247–52. [PubMed] [Google Scholar]
19. Sabuncu T, Arikan E, Tasan E, Hatemi H. Comparison of the effects of cabergoline and bromocriptine on prolactin levels in hyperprolactinemic patients. Intern Med 2001;40:857–61. [PubMed] [Google Scholar]
20. Colao A, Di Sarno A, Landi ML, Cirillo S, Sarnacchiaro F, Facciolli G, et al. Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 1997;82:3574–9. [PubMed] [Google Scholar]
21. Arduc A, Gokay F, Isik S, Ozuguz U, Akbaba G, Tutuncu Y, et al. Retrospective comparison of cabergoline and bromocriptine effects in hyperprolactinemia: A single center experience. J Endocrinol Invest 2015;38:447–53. [PubMed] [Google Scholar]
22. Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF, et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline comparative study group. N Engl J Med 1994;331:904–9. [PubMed] [Google Scholar]
23. Boguszewski CL, dos Santos CM, Sakamoto KS, Marini LC, de Souza AM, Azevedo M, et al. A comparison of cabergoline and bromocriptine on the risk of valvular heart disease in patients with prolactinomas. Pituitary 2012;15:44–9. [PubMed] [Google Scholar]
 

Tristan Loscha

Member
Thread starter
Joined
Dec 18, 2018
Messages
2,207

Mathews J Case Rep. Author manuscript; available in PMC 2019 Jun 17.
Published in final edited form as:
Mathews J Case Rep. 2019; 4(1): 42.
Published online 2019 May 8.
PMCID: PMC6578577
NIHMSID: NIHMS1019063
PMID: 31211288
A Novel Patient Case Report to Show the Successful Termination of Untreatable Androgen-independent Prostate Cancer: Treatment with Cabergoline (Dopamine agonist).
Leslie C. Costello,1 Renty B Franklin,1 and George W. Yu2
Author information Copyright and License information Disclaimer
See other articles in PMC that cite the published article.
Go to:
Abstract
Introduction:
Testosterone promotes the initial development of androgen-dependent prostate cancer. This is the basis for androgen ablation treatment, which attenuates, but does not terminate, the malignancy. Instead, it leads to prolactin-dependent malignancy; in which patient death generally occurs within 5 years. This report describes the novel treatment of a patient; which terminated androgen-independent prostate cancer.

Results:
Patient “XY” was diagnosed with prostate malignancy and metastases. He received hormonal androgen ablation treatment, chemotherapy, and radiation treatment. He developed androgen-independent prostate cancer; with expected death in 2–3 years. He was treated with cabergoline (dopamine agonist) treatment, which decreased the plasma prolactin 88%; by inhibiting the pituitary production of prolactin. The subsequent PET scan (positron emission tomography) revealed the absence of malignancy; and the CTC (circulating tumor cells) decreased from count=5.4 to count=0.

Discussion:
The cause of androgen-independent malignancy has been unknown, and an effective chemotherapy did not exist. The activities of normal and malignant prostate cells are regulated primarily by testosterone. When testosterone availability diminishes; prolactin regulation is manifested. This is represented when androgen ablation results in the development of prolactin-dependent malignancy. An effective chemotherapy would be targeted to eliminate the plasma prolactin-manifestation of the androgen-independent malignancy.

Conclusions:
This report of a novel chemotherapy for androgen-independent malignancy corroborates our understanding of the implications of prolactin in its development and treatment. There are about 165,000 cases/year with 25,000 deaths/year in the U.S.; and 1.0 million cases/year with 260,000 deaths/year worldwide. Those patients with androgen-independent prostate cancer can now employ this cabergoline treatment to prevent or terminate this deadly type of prostate cancer.

Keywords: Androgen-Independent Malignancy, Advanced Prostate Cancer, Cabergoline Treatment, Case Report
Go to:
INTRODUCTION
Advanced prostate cancer accounts for about 25,000 deaths/year in the U.S. and 260,000 deaths/year worldwide [1] Its treatment generally includes hormonal androgen ablation; which leads to androgen-independent malignancy, followed by death generally within 2–5 years. An efficacious treatment does not exist, mainly due to the poor understanding of the factors that are implicated in the development and progression of androgen-independent malignancy. Especially relevant is the issue of the hormonal regulation of normal and malignant prostate acinar epithelial cells. Costello and Franklin [2,3] have provided extensive reviews of these issues.

Testosterone and prolactin regulation of normal and malignant acinar epithelial cells: androgen ablation and the development of prolactin-dependent malignancy
The activities of the normal prostate acinar epithelial cells and their malignant cells are achieved by the dual hormonal regulation of testosterone and prolactin [4]. Generally, testosterone provides the “primary” regulation; and prolactin regulation is manifested when testosterone regulation declines. This relationship exists when testosterone ablation for the treatment of androgen-dependent prostate cancer leads to the development of androgen-independent malignancy; with a life expectancy of up to 5 years.

The cause of androgen-independent malignancy had not been established, which has deterred progress in the development of an effective treatment. This report provides corroborating evidence for our concept [2,3] that androgen-independent prostate cancer is “prolactin-dependent malignancy”. Cabergoline (dopamine agonist) has been employed to suppress the pituitary lactotropic production of prolactin in cases of hyperprolactinemia [5,6]. These relationships provided the basis for our initiation of cabergoline treatment to decrease plasma prolactin, and abort untreatable androgen-independent prostate cancer.

This is the first case report to describe an efficacious treatment of a patient that successfully aborted terminal androgen-independent prostate cancer. Notably, there were no consequential adverse side effects of the treatment. Other patients can now employ cabergoline treatment to terminate this deadly cancer.

Case history of patient “XY”, who presented with terminal androgen-independent prostate cancer
On 8/14/2017 and 9/11/2017, “XY” exhibited a prostate specific antigen (PSA)=21 and PSA= 33, respectively. Prostate biopsy on 10/1/2017 revealed Gleason grade 8 prostate cancer. This was followed by focal laser ablation of the left side of the prostate gland. The subsequent Axumin PET (positron emission tomography) showed the spread of malignancy to the right side of the prostate gland and lymph node metastasis. The oncology diagnosis was the presence of incurable malignancy; and an expected 3-year survival with hormonal androgen ablation and chemotherapy. From about 11/1/2017 – 4/1/2018; “XY” treatment included hormonal androgen ablation, chemotherapy, and radiation therapy. Beginning around 11/01/2017, androgen ablation along with chemotherapy was initiated; which included lupron, casodex, zytiga, prednisone, neulista, and Lu177-PSMA (prostate specific membrane antigen). Prior to androgen ablation, PSAs were ~20–40; and the post-androgen ablation +chemotherapy PSAs<1.0. However, the 4/18/2018 PET revealed prostate gland malignancy and extensive metastases, which represented the development of untreatable androgen-independent malignancy.

On 6/20/2018, “XY” enlisted Dr. Yu as the oncologist and Dr. Costello as the collaborating consultant to manage and treat his androgen-independent malignancy. 3% Clioquinol Cream plus 50mg zinc supplement/day along with Lu177-PSMA radiation therapy was added to the treatment of “XY”. After 8 weeks, a PET scan revealed an arrest of the androgen-dependent malignancy.

However, the persistence of untreatable terminal androgen-independent malignancy presented the major problem. We expected that the development of this malignancy was likely due to the manifestation of prolactin-dependent malignancy; as had been described by Costello and Franklin [2,3]. On 12/8/2018, cabergoline treatment (Dostinex; 0.5mg 2× week) was initiated to inhibit the pituitary production of prolactin; decrease the plasma concentration of prolactin; and terminate the prolactin manifestation of androgen-independent malignancy. After 7 weeks, the plasma prolactin concentration decreased from 11.3 ug/ml (normal prolactin level) to 1.3 ug/ml (extremely low prolactin). The 1/31/2019 MRI and PET revealed the absence of detectable malignancy. A CTCPC (circulating tumor prostate cells count) count = 5.4 on 8/27/2018, which is indicative of ~21 months of survival; and on 2/22/2019, the count=0. This reveals that the imminent death from androgen-independent metastases had been terminated. These collective results following the initiation of cabergoline treatment corroborate our concept that prolactin manifests the development and progression of androgen-independent prostate cancer. This novel case report presents a successful treatment of a patient that successfully aborted terminal androgen-independent prostate cancer.

Additional implications
The terminal androgen-independent malignancy was not aborted by the treatment with Lu177-PSMA, which is consistent with another report [7]. In contrast, the cabergoline treatment did terminate the malignancy. This suggests that the terminal androgen-independent malignant cells might not express detectable levels of PSMA, or the PSMA is mutated and not detectable.

It is also notable that the post-androgen ablation subsequent development of androgen-independent malignancy was not associated with an increase in PSA; thereby indicating that these malignant cells might not express PSA.

Those relationships are consistent with our understanding that the androgen-dependent cells and the androgen-independent cells are different populations of malignant cells.

Go to:
Acknowledgements:
Studies of LCC and RBF cited in this report were supported in part by NIH grants CA79903 and DK42839.

Go to:
Footnotes
Disclosures: Clioquinol (3% Clioquinol Cream) and cabergoline (Dostinex) treatments were in conformity with the FDA policy for the “off label use” of a clinical trial safe drug; and in conformity with the “right to try” policy for the use of the safe drug for the treatment of patients with terminal medical conditions.

Patient “XY” was presented with the manuscript for his input into the content and the publication of the manuscript.

In accordance with HIPAA policy, the authors removed identifiers (including unique patient characteristics) from the data prior to submission and publication of the article; so that a signed privacy authorization is not needed.

Go to:
REFERENCES
1. Siegel RL, Miller KD, Jemal A and Cancer statistics (2016) CA Cancer J Clin. 66: 7–30. [PubMed] [Google Scholar]
2. Costello LC and Franklin RB (2018) Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy! Oncol Rev. 12: 356. [PMC free article] [PubMed] [Google Scholar]
3. Costello LC and Franklin RB (2018) A proposed efficacious treatment with clioquinol (Zinc Ionophore) and cabergoline (prolactin dopamine agonist) for the treatment of terminal androgen independent prostate cancer. Why and how. J Clin Res Oncol. 1: 1–7. [PMC free article] [PubMed] [Google Scholar]
4. Costello LC and Franklin RB (2002) Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm Metab Res. 34: 417–424. [PMC free article] [PubMed] [Google Scholar]
5. Huang HY, Lin SJ, Zhao WG and Wu ZB (2018) Cabergoline versus bromocriptine for the treatment of giant prolactinomas: A quantitative and systematic review. Metab Brain Dis. 33: 969–976. [PubMed] [Google Scholar]
6. Yarman S, Kurtulmus N and Bilge A (2012) Optimal effective doses of cabergoline and bromocriptine and valvular leasions i n men with prolactinomas. Neuro Endocrinol Lett. 33: 340–346. [PubMed] [Google Scholar]
7. Baum RP, Kulkarni HR, Schuchardt C, Singh A, et al. (2016). 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. 7: 1006–1013. [PubMed] [Google Scholar]
 

Tristan Loscha

Member
Thread starter
Joined
Dec 18, 2018
Messages
2,207

Oncogen (Westerville). Author manuscript; available in PMC 2019 Jul 19.
Published in final edited form as:
Oncogen (Westerville). 2019; 2(3): 13.
Published online 2019 Jun 28. doi: 10.35702/onc.10013
PMCID: PMC6641560
NIHMSID: NIHMS1039812
PMID: 31328184
The Suppression of Prolactin is required for the Treatment of Advanced Prostate Cancer
Leslie C Costello
Author information Copyright and License information Disclaimer
See other articles in PMC that cite the published article.
Go to:
Abstract
Androgen-independent advanced prostate cancer is a terminal malignancy that generally results in death within five years. Its cause has been unknown, and a treatment did not exist. Prevailing views have mistakenly implicated impaired androgen receptor activity in the development of androgen-independent malignancy; which has deterred the existence of an effective treatment. Instead, recent reports have provided evidence that prolactin promotes the development and progression of androgen-independent malignancy; which follows androgen ablation treatment for androgen-dependent prostate cancer. That relationship dictates that a treatment for advanced prostate cancer should suppress the concentration plasma prolactin. This has been achieved with cabergoline (dopamine agonist; Dostinex) treatment of a patient that resulted in 88% decreased plasma prolactin, and terminated the malignancy. That likely represents the first effective treatment for advanced prostate cancer. It remains to establish if this treatment will be successful for other patients with advanced prostate cancer.

Keywords: Prolactin, Prostate Cancer, Malignancy, Metastasis
Go to:
INTRODUCTION
Androgen-independent advanced prostate cancer continues to account for most of the ~30,000 prostate cancer deaths/year in the U.S. and ~1.2 million prostate cancer deaths/year worldwide. Despite decades of research and extensive funding, an effective treatment still does not exist.

A major reason has been the confusion regarding the development and progression of advanced prostate cancer. It must first be recognized that the normal prostate acinar epithelial cells and the malignant cells are regulated by testosterone and prolactin [1,2]. Testosterone provides the “primary” hormone regulation and promotes the initiation and progression of malignancy; i.e., “androgen-dependent” prostate cancer. Androgen ablation (castrate or hormonal) treatment is employed to limit the availability of testosterone and its manifestation of malignancy. This leads to the development of “androgen-independent” malignancy; which is the status of advanced prostate cancer (castration resistant prostate cancer; CRPC). Androgen-independent advanced prostate cancer results in patient death generally in 2–5 years.

Go to:
DISCUSSION
An important unresolved issue is the cause of the development of androgen-independent malignancy. A prevailing view has focused on dysfunctional androgen receptor (inhibition of expression; mutation; impaired activity) as being implicated for the transformation of androgen-dependent malignancy to androgen-independent malignancy; and its potential as a target for an efficacious treatment. That is a mistaken understanding, which has contributed to the continued absence of an effective treatment for advanced prostate cancer.

The alternative is the recognition of the implications of prolactin in promoting the development and progression of androgen-independent advanced prostate cancer. However this relationship has been largely unrecognized and ignored by contemporary clinicians and biomedical investigators; including urologists and oncologists. This is apparent from a PubMed search of “prolactin and androgen-independent prostate cancer” that reveals only 12 citations; of which 5 were published within the recent 10 years (including Costello and Franklin [2]). The PubMed search with “prolactin and castration resistant prostate cancer” produced only 6 citations; 3 being published in the recent 10 years. Also notable is that the 2016 extensive review of prostate cancer with over 300 references makes no mention of prolactin [3].

Nevertheless, the implications of prolactin in the development of androgen-independent advanced prostate cancer has been clinically corroborated by our recent case report [4]. The patient was initially diagnosed with androgen-dependent prostate gland malignancy and lymph node metastasis. The patient had received androgen ablation treatment that included hormone therapy, chemotherapy, and radiation therapy. The androgen-dependent malignancy was terminated.

Summary of Evidence
However, androgen-independent malignancy developed; which likely is due to prolactin. Based on that expectation, cabergoline treatment (dopamine agonist; Casodex) was employed to inhibit the pituitary production of prolactin. Prior to treatment, the patient’s CTC (circulating tumor cell) count=5.4; which is indicative of survival for ~21 months. After 7 weeks treatment with cabergoline, the circulating tumor cell count=0. Correspondingly, the plasma prolactin concentration decreased 88% (11.3 to 1.3 ug/ml). This corroborates that prolactin, not impaired androgen receptor, is the required target for treating advanced prostate cancer.

Go to:
CONCLUSION
The important conclusions are: 1. The targeting for treatment of terminal advanced prostate cancer has mistakenly focused on androgen receptor as the cause of the development of advanced prostate cancer. Consequently, targeting androgen receptor has failed to result in an effective treatment. 2. Advanced prostate cancer is a prolactin-dependent malignancy. 3. An efficacious treatment should be targeted at inhibiting the pituitary lactotropic production of prolactin to suppress the plasma prolactin concentration. This has been achieved with cabergoline (dopamine agonist; Dostinex). 4. These relationships and treatment were successfully applied to a patient who presented with advanced prostate cancer; which is possibly the first reported case of an effective treatment that terminated advanced prostate cancer.

Go to:
ACKNOWLEDGEMENT
Studies of LCC cited in this report were supported in part by NIH grants CA79903 and DK42839.

Go to:
REFERENCES
1. Costello LC, Franklin RB (2002) Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm Metab Res 34(8): 417–424. [PMC free article] [PubMed] [Google Scholar]
2. Costello LC, Franklin RB (2018) Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy! Oncol Rev 12(2): 356. [PMC free article] [PubMed] [Google Scholar]
3. Packer JR, Maitland NJ (2016) The molecular and cellular origin of human prostate. Biochim Biophys Acta 1863(6 Pt A): 1238–1260. [PubMed] [Google Scholar]
4. Costello LC, Franklin RB, Yu GW (2019) A novel patient case report to show the successful termination of untreatable androgen-independent prostate cancer: Treatment with cabergoline (dopamine agonist). Mathews J Case Rep 4(1): 42. [PMC free article] [PubMed] [Google Scholar]
 
Joined
Apr 29, 2020
Messages
853
Age
59
Location
United Kingdom
So what can the average Joe do to protect their Prostate health long term?
 

Tristan Loscha

Member
Thread starter
Joined
Dec 18, 2018
Messages
2,207
So what can the average Joe do to protect their Prostate health long term?

Do everything that is stabilizing the entire organism, and if you do develop prolactine sensitive cancers, maybe try to consume long acting dopamine agonists?
 

LeeLemonoil

Member
Joined
Sep 24, 2016
Messages
2,454
Thanks for compiling, I read some of it before. Dopamine signaling emerges as a master regulator of immunity.

Nothing new for Peat, new and mind-boggling for many a pro

@Tristan Loscha

Maybe if interst: just read that Quercetin is capable of „anti-inflammatory reprogramming of the TCA/Krebs Cycle“

And it affects DHT ... maybe relevant to PC topics too

I thought some of these publications
 

Tristan Loscha

Member
Thread starter
Joined
Dec 18, 2018
Messages
2,207
So what can the average Joe do to protect their Prostate health long term?

..also making sure that zinc intake is adequate; loss of zinc in parts of the prostate seems to enable and maintain cancerosis.
@LeeLemonoil interesting, i wanted to read about it some time ago too, the compound rutin seem to be a prodrug of sorts toward quercetin.
 
Similar threads
Thread starter Title Forum Replies Date
haidut Aspirin Now Proposed As Treatment For Brain Cancer Scientific Studies 17
GorillaHead Proposed Theory: Dandruff Is A Skin Biome Imbalance. Ways To Address Proposed Symptoms, Causes 72
haidut A Proposed Anabolic Mechanism Of Tribulus Terrestris (TT) Scientific Studies 435
T Is The Proposed ''calcium Shell'' As Multiple MDs Put It From This Website Real? Miscellaneous Health Discussions 4
charlie The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report Scientific Studies 41
J Treatment for pericoronitis Oral Health 0
Pina Topical Lung T3 Treatment COVID-19 Acute Respiratory Distress Syndrome Thyroid and Hormones 0
haidut Androgens (e.g. DHT) curative even for treatment-resistant breast cancer Scientific Studies 0
Mito The efficacy of Vitamin K in the treatment of cancer K 1
N Diamant / Adamantane usage as an anti-viral in the treatment of covid19? Ask For Help or Advice 0
egoy What do we know untill now about autism solutions,treatment? Autism 31
haidut Another COVID-19 Treatment Trial Halted For Safety Reasons Miscellaneous Health Discussions 34
M Thoughts On PSSD And Possible Treatment Male Issues 4
M Inflamatory Breast Cancer Treatment Causes? Female Issues 1
haidut Eli Lilly's Trial For COVID-19 Antibody Treatment Halted For Safety Reasons Miscellaneous Health Discussions 33
L Hair Growth From Thyroid Treatment Hair & Nails 10
S Treatment For Fungus/yeast/candida? Help Plz Ask For Help or Advice 45
Tristan Loscha Effect Of Calcifediol (VIT D) Treatment And Best Available Therapy Versus Other On ICU + Survival D 1
Mito LLLT Using A Helmet-type Device For The Treatment Of Androgenetic Alopecia Red Light, Infrared, LLLT 1
S MPB Treatment : Apirin And Castor Oil Combo Hair & Nails 5
L T3 Only Hypothroid Treatment Metabolism 4
Max23 Budesonide - Another Covid Treatment Health 6
DJ123 Is This Legit Treatment For Glaucoma? Eyes, Ears, Nose and Headaches/Migraines 3
Epistrophy 1976 Russian Treatment For Coronavirus Scientific Studies 12
C Kenneth Blanchard On Optimal Hypothyroidism Treatment Thyroid and Hormones 80
Tristan Loscha Severe And Persistent Thyroid Dysfunction Associated With Tetracycline-Antibiotic Treatment In Youth Pharmaceutical Drugs 45
burtlancast US Government Scared To Death Of Vit C Treatment By I.V. For Coronavirus Miscellaneous Health Discussions 3
S.Seneff COVID-19: Melatonin As A Potential Adjuvant Treatment Scientific Studies 4
md_a Angiotensin Receptor Blocker (ARB) Drugs For Potential Repurposing Treatment Of 2019-nCoV Infection Scientific Studies 0
S Chinese Handbook Of COVID-19 Prevention And Treatment Health 0
A Possibly The Best Treatment For Rheumatoid Patients Health 10
ecstatichamster Chloroquine Is Very Harmful As A Covid-19 Treatment - Why Are They Touting It? Supplements, Pharmaceutical Drugs 17
E Corona / COVID-19 : Prevention And Treatment - The Official Chinese Handbook (eBook) Health 2
haidut Inosine For The Treatment Of COVID-19 Scientific Studies 36
Soren Uncle Has Cancer Help With Treatment Advice Cancer, Degenerative Diseases 36
yerrag Japanese Kampo Medicines For The Treatment Of Common Diseases: Focus On Inflammation By Amazon.com S Book Recommendations 7
SuicideNote PSSD Treatment Mental Issues 6
Soren Cyst In Glute Muscle, Infected Treatment Help Symptoms, Causes 0
haidut Aspirin Safe And Effective For Prevention AND Treatment Of Migraine Scientific Studies 6
N Ultrasound As A Cancer Treatment! Interesting Discussion Scientific Studies 6
DannyIrons™ Advice On Antibiotic Treatment Ask For Help or Advice 5
Mito Late Life Metformin Treatment Limits Cell Survival And Shortens Lifespan Articles & Scientific Studies 6
Evgenij Treatment For Leanness (Dr. Paul Berger, Berlin 1890) Articles & Scientific Studies 2
ecstatichamster Forgotten Treatment: Testosterone And Progesterone Prevent Cancer Scientific Studies 1
Z Psoriasis Treatment, Dietary Advice Skin 10
Summer Need Treatment Advice For Wound That Won't Heal Skin 6
Y IP6K3 Gene Deletion Mice Extended Lifespan And IP6K3 Was Upregulated By Dexamethasone Treatment Cortisol, Serotonin, Histamine 5
P Methylene Blue As A Treatment Of Cyanide Intoxication Methylene Blue 0
haidut Allopregnanolone As A Treatment Of Alzheimer Disease (AD) Scientific Studies 0
Lokzo Donkey Milk (Equus Asinus) As A Potential Treatment Strategy For Type 2 Diabetes Scientific Studies 16

Similar threads

Top