Haruo Kato

Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins

Background There are some reports about the antitumor effects of statins in these days. Statins decrease the level of cholesterol in the blood by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Inhibition of this enzyme decreases intracellular cholesterol synthesis. Thus, the expression of low-density lipoprotein receptor (LDLr) is increased to import more cholesterol from the bloodstream. In this study, we assessed the effects of statins on the proliferation of prostate cancer cells, and studied the relationship between the expression of LDLr and the effects of statins. Methods Simvastatin was used in the experiments. We studied the effect of simvastatin on PC-3 and LNCaP cell proliferation using the MTS assay, and evaluated the expression of LDLr after administration of simvastatin by quantitative polymerase chain reaction and Western blotting. Intracellular cholesterol levels in the prostate cancer cells were measured after administration of simvastatin. Furthermore, small interfering RNA (siRNA) was used to knockdown the gene expression of LDLr. Results In PC-3 cells, simvastatin inhibited cell proliferation. In LNCaP cells, only a high concentration of simvastatin (100μM) inhibited cell proliferation. In LNCaP cells, the protein level of LDLr was increased by simvastatin. In PC-3 cells, the protein levels of LDLr were unregulated. In PC-3 cells, but not in LNCaP cells, intracellular cholesterol levels were significantly decreased by simvastatin. After knocking down LDLr expression by siRNA, intracellular cholesterol levels were decreased, and cell proliferation was inhibited by simvastatin in LNCaP cells. Conclusion Simvastatin inhibited prostate cancer cell growth by decreasing cellular cholesterol and could be more effective in androgen-independent prostate cancer, where there is loss of regulation of LDLr expression. LDLr was shown to play an important role in the statin-induced inhibition of prostate cancer cell proliferation. These results suggest that future studies evaluating the cholesterol-lowering effects of statin may lead to new approaches to the prevention and treatment of prostate cancer.

Clinical endocrinological evaluation of the gonadal axis (testosterone, LH and FSH) in prostate cancer patients switched from a GnRH antagonist to a LHRH agonist

ObjectivesTo investigate the levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prostate-specific antigen (PSA) in prostate cancer patients before and after the switch from degarelix to leuprolide treatments.MethodsWe enrolled 40 treatment-naïve prostate cancer patients who were treated initially with degarelix and were later switched to leuprolide. The subjects were divided into three groups depending on when they were switched to leuprolide: the 3-month group (3m; switched after 84 days, n=10), the 2-month group (2m; 56 days, n=10), and the 1-month group (1m; 28 days, n=20). Patient symptoms and hormone levels were measured after switching therapy. The castration level was defined as a serum testosterone level ≤50 ng/dl.ResultsThirty-nine subjects (97.5%) achieved castration levels of testosterone (11±5.8 ng/dl) 2 weeks after degarelix was first administered, and the characteristics of these patients were investigated. Testosterone levels increased and exceeded the castration level in one subject each of the 3m (142 ng/dl), 2m (72 ng/dl), and 1m groups (63 ng/dl). All subjects achieved the castration level by day 5. In contrast to testosterone levels, the LH and FSH surge on day 2 was significantly higher in the 1m group than in the other groups. The clinical symptoms were not exacerbated before or after switching in any patients.ConclusionsA testosterone surge was observed in 8.3 % of the study patients; however, it was very short-lived and mild. LH and FSH levels were significantly higher 1 month after administration compared with 2 or 3 months after degarelix administration.

Simvastatin up-regulates annexin A10 that can inhibit the proliferation, migration, and invasion in androgen-independent human prostate cancer cells

Statins have recently been studied for their proapoptotic and antimetastatic effects. However, the exact mechanisms of their anticancer actions remain unclear. Using microarrays, we discovered up‐regulation of annexin A10 (ANXA10) in PC‐3 cells after simvastatin treatment. ANXA10 reportedly has antitumor effects. In this study, we evaluated the effects of simvastatin on ANXA10 signaling in androgen‐independent prostate cancer cells.

Efficacy of Indocyanine Green Angiography on Microsurgical Subinguinal Varicocelectomy

ABSTRACT Objectives: Microsurgical subinguinal varicocelectomy is one of the best treatment modalities for varicoceles related to male infertility and scrotal pain. However, the difficulty in identifying testicular arteries, which should be spared, is a limitation of this technique. To visualize and identify the testicular arteries in spermatic cord during the operation, we examined the efficacy of intraoperative indocyanine green angiography (ICGA), which is regularly used in microsurgical neurosurgery. Methods: After the exposure of the spermatic cord blood vessels, ICG was injected intravenously under a surgical microscope for observing infrared fluorescence in patients to identify and isolate the testicular artery. Results: The testicular artery was clearly identified by ICGA and was able to separate under ICGA view. Thereafter, the varicose veins were repeatedly ligated, while preserving a few lymphatic vessels and the spermatic duct. The preserved arteries were confirmed by repeated ICGA at the end of microsurgical operation. The number of arteries identified by ICGA was greater than the number detected by preoperative computed tomography angiogram. Conclusions: Microsurgical subinguinal varicocelectomy using intraoperative ICGA facilitated safe and quick surgery by enabling the visualization of the spermatic cord blood vessels. This is the first report to indicate the usefulness of vessel visualization by ICGA during microsurgical subinguinal varicocelectomy.

Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC‑3 cells via an AKR1C3 mechanism

Statins have become of interest in research due to their anticancer effects. However, the exact mechanism of their anticancer properties remains unclear. The authors previously reported that statins decrease intracellular cholesterol levels in androgen-independent prostate cancer cells. In de novo androgen synthesis, cholesterol is the primary material and certain enzymes have important roles. The present study aimed to determine whether simvastatin alters the expression of androgen synthesis-associated enzymes in androgen-independent prostate cancer cells. A novel combination therapy of statins and other drugs that inhibit the overexpression of enzymes involved in androgen synthesis was explored. The cytotoxicity of simvastatin and meclofenamic acid was assessed in prostate cancer cells using MTS and migration assays. Testosterone and dihydrotestosterone concentrations in the culture medium were measured using liquid chromatography-tandem mass spectrometry. RAC-α-serine/threonine-protein kinase (Akt) phosphorylation was detected by western blot analysis. Following treatment with simvastatin, aldo-keto reductase family 1 member C3 (AKR1C3) expression increased in PC-3 (>60-fold) and LNCaP-LA cells, however not in 22Rv1 cells. Small interfering (si)RNA was used to clarify the effects of AKR1C3 expression. The reduction in AKR1C3 expression in PC-3 cells following siRNA transfection was not associated with basal cell proliferation and migration; however, treatment with simvastatin decreased cell proliferation and migration. The combination of simvastatin and meclofenamic acid, an AKR1C3 inhibitor, further enhanced the inhibition of cell proliferation and migration compared with treatment with either drug alone. Furthermore, treatment with simvastatin attenuated insulin-like growth factor 1-induced Akt activation; however, the combination of simvastatin and meclofenamic acid further inhibited Akt activation. These results suggest that the combination of simvastatin and meclofenamic acid may be an effective strategy for the treatment of castration-resistant prostate cancer.