tacrolimus and Prostatic-Neoplasms

Radical prostatectomy (RP) is associated with erectile dysfunction, largely mediated through cavernous nerve injury. There are robust pre-clinical data supporting a potential role for neuromodulatory agents in this patient population. This study assessed tacrolimus in improving erectile function recovery rates after RP (ClinicalTrials.gov number, NCT00106392).. To define the utility of oral tacrolimus in improving erectile function recovery after nerve sparing radical prostatectomy.. A randomized, double-blind trial compared tacrolimus 2-3 mg daily and placebo in men undergoing RP. Patients had localized prostate cancer and excellent baseline erectile function, underwent bilateral nerve-sparing RP, and were followed up for at least 18 months after RP. Patients received study drug for 27 weeks and completed the International Index of Erectile Function erectile function domain (EFD) questionnaire at baseline and serially after surgery.. International Index of Erectile Function erectile function domain score.. Data were available for 124 patients (59 tacrolimus, 65 placebo); mean age was 54.6 ± 6.2 years. No patient experienced permanent creatinine or potassium elevation. At baseline, mean EFD scores were 28.6 ± 2.1 (tacrolimus group) and 29 ± 1.5 (placebo group). By week 5, mean EFD scores had dropped to 8 ± 9.4 (tacrolimus) and 9 ± 10.7 (placebo). At 18 months, mean EFD scores were 16.0 ± 11.3 (tacrolimus) and 20.2 ± 9.0 (placebo) (P = .09). Tacrolimus failed to meet significance (hazard ratio = 0.83; P = .50), with no difference in: (i) percentage of patients achieving normal spontaneous erectile function (EFD score ≥24), (ii) time to normalization of EFD score (≥24), (iii) percentage of patients capable of intercourse in response to phosphieserase type 5 inhibitor (PDE5i), and (iv) time to achieve response to PDE5i.. Despite positive animal data, oral tacrolimus as used in this trial failed to improve erectile function after nerve sparing radical prostatectomy.. The study is limited by a high attrition rate. The strengths include a randomized, placebo controlled design, extensive patient monitoring, use of medication diaries and a validated instrument as the primary outcome measure.. Despite supportive animal data, tacrolimus used in this fashion in the RP population failed to demonstrate any superiority over placebo. Mulhall JP, Klein EA, Slawin K, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy. J Sex Med 2018;15:1293-1299.

Topics: Aged; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Neurotransmitter Agents; Penile Erection; Postoperative Complications; Prostatectomy; Prostatic Neoplasms; Recovery of Function; Surveys and Questionnaires; Tacrolimus; Treatment Outcome; United States

Hypomagnesemia with urinary magnesium wasting is a well described adverse event with calcineurin inhibitor therapy. Prostate cancer is the most prevalent cancer in men in the United States. Injury to the cavernous nerves during radical prostatectomy frequently results in erectile dysfunction. Tacrolimus has been shown to be neuroprotective in the rat cavernous nerve injury model, an animal model representative of the neural injury that occurs in humans at the time of radical prostatectomy.. In a randomized, double-blind, placebo-controlled trial, the utility of tacrolimus was assessed for prevention of erectile dysfunction following bilateral nerve-sparing radical prostatectomy.. Low dose tacrolimus, associated with low trough levels, resulted in mild hypomagnesemia, which was an early and persistent finding. As early as one week after institution of therapy, mean and median serum magnesium levels were significantly lower in the tacrolimus arm as compared to the placebo arm (p<0.001 for both). While the mean and median levels were within the normal range at Week 1, 10.9% of tacrolimus-treated patients had levels <1.8mg/dL, compared to none in the placebo arm (p=0.017). Median and mean levels remained significantly different at Week 5, Month 3 and Month 6. No clinical manifestations of hypomagnesemia were noted and no subject required treatment with magnesium. Changes in serum magnesium occurred earlier than other potential metabolic adverse events described with tacrolimus (changes in serum glucose, creatinine or potassium).. These data indicate that mild hypomagnesemia is an early and sensitive biomarker for the effect of tacrolimus on the kidney.

Topics: Calcineurin Inhibitors; Double-Blind Method; Erectile Dysfunction; Humans; Magnesium; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms; Tacrolimus

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Drug Therapy, Combination; Humans; Lymphohistiocytosis, Hemophagocytic; Male; Prostatic Neoplasms; Steroids; Tacrolimus; Treatment Outcome

Topics: Erectile Dysfunction; Humans; Male; Organ Sparing Treatments; Penile Erection; Prostatectomy; Prostatic Neoplasms; Tacrolimus

The functional role of nuclear factor of activated T-cells (NFAT), a well-characterized regulator of the immune response, in prostate cancer progression remains largely unknown. We aim to investigate biological significance of NFATc1, a NFAT isoform shown to function as an oncogene in a sarcoma model, in human prostate cancer.. We first determined the expression levels of NFAT in prostate cell lines and tissue specimens. We then assessed the effects of NFAT inhibition via NFATc1-small interfering RNA (siRNA) as well as immunosuppressants including cyclosporine A (CsA) and tacrolimus (FK506) on prostate cancer cell proliferation, apoptosis, migration, and invasion in vitro and in vivo.. Immunohistochemistry revealed that the expression levels of NFATc1 were significantly elevated in prostatic carcinomas, compared with non-neoplastic prostate or high-grade prostatic intraepithelial neoplasia tissues, and in high-grade (Gleason scores ≥7) tumors. NFATc1 positivity in carcinomas, as an independent prognosticator, also correlated with the risk of biochemical recurrence after radical prostatectomy. In prostate cancer cell lines, CsA and FK506 inhibited NFATc1 expression and its nuclear translocation, NFAT transcriptional activity, and the expression of c-myc, a downstream target of NFAT. NFAT silencing or treatment with these NFAT inhibitors resulted in decreases in cell viability/colony formation and cell migration/invasion, as well as increases in apoptosis, in androgen receptor (AR)-negative, AR-positive/androgen-sensitive, and AR-positive/castration-resistant lines. No significant additional inhibition in the growth of NFAT-siRNA cells by CsA and FK506 was seen, whereas these agents, especially FK506, further inhibited their invasion. In xenograft-bearing mice, CsA and FK506 significantly retarded tumor growth.. Our results suggest that NFATc1 plays an important role in prostate cancer outgrowth. Thus, NFATc1 inactivation, especially using CsA and FK506, has the potential of being a therapeutic approach for not only hormone-naïve but also castration-resistant prostate cancers.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclosporine; Disease Progression; Humans; Male; Mice; Neoplasm Invasiveness; NFATC Transcription Factors; Prostatic Neoplasms; Tacrolimus; Xenograft Model Antitumor Assays

Hemorrhagic cystitis is a rare and severe late complication of pelvic radiation, and there is no regulatory-approved drug treatment. We present an 81-year-old man with a history of localized prostate cancer, which was treated with external beam radiation therapy and subsequently developed severe hemorrhagic radiation cystitis for which he has failed several treatments. We present the novel use of intravesical tacrolimus for the treatment of refractory radiation cystitis and gross hematuria. The patient tolerated the treatment well, and it resulted in the resolution of his gross hematuria without further consideration for formalin instillation or cystectomy and diversion. Intravesical tacrolimus is a safe, minimally invasive, and promising treatment option for radiation hemorrhagic cystitis.

Topics: Administration, Intravesical; Aged, 80 and over; Calcineurin Inhibitors; Cystitis; Hematuria; Humans; Male; Prostatic Neoplasms; Radiation Injuries; Radiotherapy; Tacrolimus

Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa.

Topics: Androgens; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cyclophilins; Cyclosporine; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Immunosuppressive Agents; Male; Metribolone; Prostatic Neoplasms; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tacrolimus; Tacrolimus Binding Proteins

In kidney recipients, the immunosuppressant sirolimus has been associated with a decreased incidence of de novo posttransplant malignancies (including prostate cancer). But the effect of sirolimus on the prostate-specific antigen (PSA) blood level, an important prostate cancer screening tool, remains unknown. We studied male kidney recipients >50 years old (transplanted from January 1994 to December 2006) without clinical evidence for prostate cancer. Pre- and posttransplant PSA levels were analyzed for 97 recipients (n = 19 on sirolimus, n = 78 on tacrolimus [control group]). Pretransplant PSA was similar for sirolimus versus tacrolimus recipients (mean, 1.8 versus 1.7 ng/mL, p = 0.89), but posttransplant PSA was significantly lower for recipients on sirolimus (mean, 0.9 versus 1.9 ng/mL, respectively, p < 0.001). The mean difference between pretransplant and posttransplant PSA was -0.9 ng/mL (50.0%, p = 0.006) for the sirolimus group versus +0.2 ng/mL (+11.8%, p = 0.24) for the tacrolimus group. By multivariate analysis, only pretransplant PSA and immunosuppression with sirolimus independently impacted posttransplant PSA. Our data strongly suggest that sirolimus is associated with a significant PSA decrease in kidney recipients. Future studies must investigate the clinical implications of our findings for the use of PSA for prostate cancer screening in male kidney recipients on sirolimus.

Topics: Case-Control Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mass Screening; Middle Aged; Multivariate Analysis; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation

The androgen receptor (AR) contributes to growth of prostate cancer even under conditions of androgen ablation. Thus, new strategies to target AR activity are needed. The AR interacts with the immunophilin FK506-binding protein 52 (FKBP52), and studies in the FKBP52 knockout mouse have shown that this protein is essential to AR activity in the prostate. Therefore, we tested whether the immunophilin ligand FK506 affected AR activity in prostate cancer cell lines. We also tested the hypothesis that the AR interacts with another immunophilin, cyclophilin 40 (Cyp40), and is regulated by its cognate ligand cyclosporin A (CsA). We show that levels of FKBP52, FKBP51, Cyp40, and a related co-chaperone PP5 were much higher in prostate cancer cells lines [(LNCaP), PC-3, and DU145] compared with primary prostate cells, and that the AR of LNCaP cells can interact with Cyp40. In the absence of androgen, CsA caused inhibition of cell growth in the AR-positive LNCaP and AR-negative PC-3 and DU145 cell lines. Interestingly, FK506 only inhibited LNCaP cells, suggesting a dependence on the AR for this effect. Both CsA and FK506 inhibited growth without inducing apoptosis. In LNCaP cells, CsA completely blocked androgen-stimulated growth, whereas FK506 was partially effective. Further studies in LNCaP cells revealed that CsA and FK506 were able to block or attenuate several stages of AR signaling, including hormone binding, nuclear translocation, and activity at several AR-responsive reporter and endogenous genes. These findings provide the first evidence that CsA and FK506 can negatively modulate proliferation of prostate cells in vitro. Immunophilins may now serve as new targets to disrupt AR-mediated prostate cancer growth.

Topics: Androgens; Biological Transport; Cell Division; Cell Line, Tumor; Cell Nucleus; Cyclophilins; Cyclosporine; Dihydrotestosterone; Humans; Immunophilins; Ligands; Male; Nuclear Proteins; Peptidyl-Prolyl Isomerase F; Phosphoprotein Phosphatases; Prostatic Neoplasms; Receptors, Androgen; Tacrolimus; Tacrolimus Binding Proteins; Transcription, Genetic

Rats transplanted with the androgen-sensitive, syngeneic Dunning R3327 PAP prostatic tumor were castrated and treated with estrogen or vehicle for 4, 12 and 24 hr and for 6 weeks. Tumor growth was retarded by castration and further inhibited by estrogen. Immediately after castration, an increased number of activated macrophages and T-cells were found in parallel with increasing apoptotic tumor cells. Administration of an immunosuppressive drug, FK 506, abolished the growth-inhibitory effects of castration and estrogen. The tumor growth rate correlated negatively with the number of R73- and OX8-positive T-cells and NK cells and with the percentage of ED3-positive macrophages. There was a positive correlation between the percentage of TdT-mediated-dUTP nick end labeling (TUNEL)-positive apoptotic cells and that of ED3-positive cells. Our results suggest that apoptosis of prostatic carcinoma cells induced by endocrine treatment in vivo is partly due to a rapid infiltration by immunocompetent cells.

Topics: Adenocarcinoma; Animals; Apoptosis; Cell Division; Estradiol; Immunosuppressive Agents; Killer Cells, Natural; Macrophage Activation; Macrophages; Male; Orchiectomy; Prostatic Neoplasms; Rats; T-Lymphocytes, Cytotoxic; Tacrolimus; Tumor Cells, Cultured