Caspase 3 expression in benign prostatic hyperplasia and prostate carcinoma.

BACKGROUND: Apoptotic resistance to androgen ablation represents a significant problem in the treatment of prostate cancer. Over expression of antiapoptotic proteins such as Bcl-2 and mutations in p53 contribute to this resistance. The caspase family of proteases are central executioners of the cell death pathway. They are expressed in normal prostate secretory epithelial cells. Altered expression may represent an additional component leading to cell resistance. The aim of this study was to determine by immunohistochemistry caspase 3 expression in benign prostatic hyperplasia and prostate cancers. METHODS: Twenty-two patients with histologically determined prostate cancer and benign prostatic hyperplasia (BPH) were investigated. All specimens were obtained from patients undergoing surgical resection of the prostate. Immunohistochemical analysis was performed on formalin fixed paraffin embedded sections to assess caspase 3 expression. RESULTS: Caspase 3 was expressed in 18/22 (81.1%) samples, with high expression in BPH which demonstrated staining in both basal and secretory epithelial cells. Increasing grades of prostatic cancer showed a significant loss of expression in secretory epithelial layers and little staining in epithelial cells in high-grade prostatic carcinoma. CONCLUSIONS: Altered caspase 3 expression may represent an additional mechanism of apoptotic resistance to androgen ablation. Prostate 47:183-188, 2001.

Nitric oxide in unilateral ureteral obstruction: effect on regional renal blood flow.

BACKGROUND: Ureteral obstruction (UO) is characterized by reduced blood flow and loss of tissue mass in the involved kidney(s). Vasoactive mediators interact to produce an initial hyperemia, followed by a sustained decrease in renal blood flow in the obstructed kidney. Nitric oxide (NO) has been shown to play a central role in the acute hyperemic response to UO. Its role in the reduced perfusion of prolonged UO is less studied. METHODS: Ureteral obstruction was achieved by ligation of the distal left ureter and maintained for 24 hours. Blood flow was studied in untreated animals and after the administration of the NO synthase (NOS) inhibitor N-mono-methyl L-arginine and the NO donor sodium nitroprusside. Tissue was collected for localization and quantitation of NOS. Serum and renal tissue L-arginine levels were measured in control and UO settings. RESULTS: Blood flow in the obstructed kidney diminished to approximately 50% of control values after 24 hours of UO. NOS blockade led to a further decrease in blood flow. Supplementation with exogenous nitrates restored renal blood flow to levels approaching control values. Serum and tissue L-arginine levels did not change with UO. NOS expression was seen to increase with increasing duration of obstruction, with staining most pronounced in the renal tubules. CONCLUSIONS: NO plays a vasodilatory role even in the hypoperfusion of prolonged UO. The administration of exogenous nitrates has a restorative effect on blood flow, suggesting therapeutic potential in UO.

Sexual function in patients with benign prostatic hyperplasia.

Sexual health has significant impact on quality of life among men with benign prostatic hyperplasia (BPH). The degree of sexual dysfunction matches the severity of lower urinary tract symptoms (LUTS). Treatment of BPH affects not only LUTS, but sexual function as well. Medical, surgical, and minimally invasive therapies differ in their effect on erectile function, ejaculation, and sexual satisfaction. Choice of treatment modality takes into account baseline sexual function and patient expectations. This review outlines the relationship between LUTS and sexual function and how they change with the currently available treatments.

Glutathione depletion-induced neutrophil apoptosis is caspase 3 dependent.

Resolving inflammation is a vital step in preventing the persistence of inflammatory disorders. Neutrophils play a major role in tissue damage associated with an inflammatory response. Their death by apoptosis is central to the final resolution of this response. Thiol depletion with diethylmaleate (DEM) or diamide represent important triggers for neutrophil apoptosis. The mechanism by which this process occurs remains unknown. The apoptotic cascade is associated with a number of cellular changes, including caspase activation and mitochondrial permeability. The aims of this study were to determine the role of mitochondrial permeability and the caspase cascade in thiol depletion-induced neutrophil apoptosis. Total cellular glutathione was reduced by DEM and diamide. This reduction was associated with neutrophil apoptosis and an increase in caspase 3 activity. The effects of DEM were blocked by the caspase 3 inhibitor, Z-DEVD-FMK. Mitochondrial permeability that occurred was also increased during this induction of apoptosis. Bongkrekic acid, a mitochondrial membrane stabilizer, inhibited DEM-induced apoptosis. The inhibitors' effects of LPS or GM-CSF on spontaneous neutrophil apoptosis was reversed by DEM, which was mediated by an increase in caspase 3 activity and independent of mitochondrial disruption. Caspase activation is an important step in glutathione depletion-induced apoptosis in resting and inflammatory neutrophils. Regulation of caspase activity may represent a possible target to trigger apoptosis and resolve inflammatory disorders.

Thiol-mediated apoptosis in prostate carcinoma cells.

BACKGROUND: Glutathione (GSH) maintains an optimum cellular redox potential. Chemical depletion, physical efflux from the cell, or intracellular redistribution of this thiol antioxidant is associated with the onset of apoptosis. The aim of this study was to determine the effects of a thiol-depleting agent, diethylmaleate (DEM), on androgen sensitive and insensitive prostate carcinoma cells. METHODS: LNCaP and PC-3 cell lines were induced to undergo apoptosis by DEM and diamide. Apoptosis was quantified by annexin V binding and propidium iodide incorporation using flow cytometry and was confirmed by DNA gel electrophoresis. Intracellular GSH was quantified using a thiol quantitation kit and the generation of reactive oxygen intermediates was measured using dihydrorhodamine 123. Western blot assessed caspase-3, caspase-8, Bcl-2, and Bcl-XL protein expression. Mitochondrial permeability was measured using DiOC6 and stabilized using bongkrekic acid. RESULTS: DEM and diamide induced apoptosis in both androgen sensitive and insensitive cells. Apoptosis was also induced in an LNCaP transfectant cell line overexpressing Bcl-2. Apoptosis was caspase-3 dependent and caspase-8 independent. Bongkrekic acid partially prevented the effects of DEM on mitochondrial permeability but was unable to prevent the induction of apoptosis. Decreased Bcl-2 and Bci-XL protein expression was observed at the time of initial caspase-3 activation. CONCLUSIONS: This study demonstrates that thiol depletion can be used as an effective means of activating caspase-3 in both androgen sensitive and insensitive prostate carcinoma cells. Direct activation of this effector caspase may serve as a useful strategy for inducing apoptosis in prostate carcinoma cells.

Future prospects in prostate cancer.

BACKGROUND: Prostate cancer has displayed an increase in incidence unparalleled by any other tumor in the last two decades, with a steady, more gradual increase in mortality rate. Current curative strategies are focused on the detection and treatment of early-stage (T1-2 N0 M0), clinically significant tumors. METHODS: To this aim, refinement of surgical approaches, with appropriate adjuvant therapies, will ensure more complete cancer control, while minimizing associated morbidity. New delivery systems for radiotherapy, as well as other energy sources, are evolving, while a number of promising pharmacological agents, including angiogenesis inhibitors and drugs which alter signal transduction pathways, are currently under investigation. Early detection is also being facilitated by a more widespread implementation of screening programs. Advances in tumor markers, and imaging and biopsy techniques, will allow more accurate preoperative staging. These, coupled with improvements in prognostic markers, aid the physician and patient alike in deciding on the suitability of treatment options with better estimation of outcome. Perhaps the most exciting developments in prostate cancer will come from knowledge of the molecular mechanisms underlying carcinogenesis. The potential for the development of diagnostic and therapeutic tools is immense. The efficacy of treatment can be studied at a molecular level, and strategies for preventing or slowing the development of malignancy can be formulated. RESULTS AND CONCLUSIONS Application of this knowledge in the form of gene and cellular therapy and in the development of novel systemic agents is beginning to enter the realm of clinical practice, and it may be in this field that means for cure and prevention of prostate cancer will eventually be found.

High intensity focused ultrasound in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is an extremely common condition and represents a major health issue in terms of patient numbers and treatment cost. Traditionally, the choice of treatment has been between watchful waiting and surgery, however, the side effects of surgery lead to reluctance for treatment in many men, other than those with severe symptoms and complications. In the last 2 decades there has been a rapid expansion in the number of treatments being offered and the number of patients submitting to novel therapies. Medical management has evolved to achieve a central role in the management of BPH. Heat based treatments are also being investigated with considerable interest. Transrectal high intensity focused ultrasound (HIFU) is one such treatment, which allows radiation-free treatment, without the need for intra-urethral manipulation. Imaging can be performed during treatment and treatment results in symptomatic improvement, which is retained with medium-term follow-up. It involves a brief hospital stay and post-operative complications are few. The use of HIFU has also been extended to the treatment of renal, prostatic and bladder tumours and the results in these areas suggest further expansion of its role in urological practice.

Obstructive uropathy.

Recent study has increased the understanding of the physiological processes occurring in obstructive uropathy, in particular the role played by vasoactive mediators and cellular mechanisms. There is an emphasis on developing effective and less invasive means of detection and treatment of ureteric obstruction, although it remains to be determined how the techniques currently being assessed will impact on clinical practice.