NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128.

Prostate cancer stem cells (CSCs) are defined by their extensive self-renewal, differentiation and tumor initiation properties. It is now clear that CSCs are involved in tumor growth and recurrence, and resistance to conventional treatments. The sonic hedgehog (Shh) pathway has a crucial role in stemness and tumorigenesis. Thus, the strategy that suppresses stemness and consequently tumorigenic potential of CSCs could be considered for the management of prostate cancer. The objectives of this study were to examine the molecular mechanisms, by which NVP-LDE-225/Erismodegib (smoothened inhibitor) regulates stem cell characteristics and tumor growth in prostate cancer. The effects of NVP-LDE-225 on CSC's viability, sphere formation, apoptosis, epithelial-mesenchymal transition (EMT) and tumor growth in NOD/SCID IL2Rγ null mice were examined. NVP-LDE-225 inhibited cell viability and spheroid formation, and induced apoptosis by activation of caspase-3 and cleavage of poly-ADP ribose polymerase (PARP). NVP-LDE-225 induced expression of Bax and Bak, and inhibited the expression of Bcl-2, Bcl-XL, XIAP, cIAP1, cIAP2 and survivin. NVP-LDE-225 inhibited Gli transcriptional activity, Gli-DNA interaction and the expression of Gli1, Gli2, Patched1 and Patched-2 in prostate CSCs. Interestingly, NVP-LDE-225 induced PDCD4 and apoptosis and inhibited cell viability by suppressing miR-21. Furthermore, NVP-LDE-225 inhibited pluripotency-maintaining factors Nanog, Oct-4, c-Myc and Sox-2. The inhibition of Bmi-1 by NVP-LDE-225 was regulated by upregulation of miR-128. NVP-LDE-225 suppressed EMT by upregulating E-cadherin and inhibiting N-cadherin, Snail, Slug and Zeb1 by regulating the miR-200 family. Finally, NVP-LDE-225 inhibited CSC tumor growth, which was associated with the suppression of Gli1, Gli2, Patched-1, Patched-2, Cyclin D1, Bmi-1 and PCNA and cleavage of caspase-3 and PARP in tumor tissues derived from NOD/SCID IL2Rγ null mice. Overall, our findings suggest that inhibition of the Shh signaling pathway could therefore be a novel therapeutic option in treating prostate cancer.

Effects of soy phytoestrogens on the prostate.

Worldwide disparities exist between geographic regions with regard to prostate cancer incidence and mortality. Countries in East Asia have lower rates of prostate cancer compared with Western countries such as Canada and the US. Some suggest that dietary differences between the two geographic regions, particularly the higher amount of phytoestrogens consumed in East Asia, is responsible for the difference in prostate cancer incidence. The mechanism of action of the soy isoflavones is incompletely understood, but in regards to prostate carcinogenesis likely involves estrogenic effects, cell cycle inhibition, anti-angiogenesis and induction of apoptosis. Recent clinical studies have provided mixed results with regard to a clear association between prostate cancer and soy consumption. Further studies are needed to understand more clearly the relationship between soy consumption and prostatic diseases.

Treatment of vitamin D deficiency in patients with metastatic prostate cancer may improve bone pain and muscle strength.

PURPOSE: We performed a phase II study to determine whether pain associated with prostate cancer bone metastasis would respond to vitamin D replacement and parameters of muscle strength would be improved by vitamin D replacement therapy. MATERIALS AND METHODS: After a 4-week placebo period, eligible patients received orally 2,000 units vitamin D daily for 12 weeks. Pain questionnaires and measurements of muscle strength were competed at study enrollment and every 4 weeks thereafter. Serum calcium and vitamin D were measured at each clinic visit. RESULTS: A total of 16 patients with advanced hormone refractory prostate cancer were enrolled in this phase II study, of whom 7 (44%) had decreased baseline vitamin D. With vitamin D treatment, 4 patients (25%) had improvement in pain scores and 6 (37%) had improvement in muscle strength measurements. Improvement in pain scores correlated with improvement in subjective symptoms but did not result in a significant decrease in regular scheduled analgesic requirements. CONCLUSIONS: Vitamin D deficiency develops in a significant percent of patients with advanced hormone refractory prostate cancer. Supplementation with vitamin D may be a useful adjunct for improving pain, muscle strength and quality of life in this patient population.

Urokinase-type plasminogen activator expression in human prostate carcinomas.

The prostate gland is the most common site of cancer in men in the United States. The biologic behavior of an individual tumor, however, varies widely, with some cancers taking a relatively indolent course and other progressing rapidly to disseminated disease. Prognostic factors that might help predict a tumor's aggressiveness and invasiveness are limited. The expression of urokinase plasminogen activator was evaluated in 36 human prostate cancer specimens. Using an immunohistochemical method with monoclonal antibody #394, 70.6% (12 of 17) of cancer specimens with extracapsular extension showed increased expression of urokinase plasminogen activator, compared with 26.6% (4 of 15) of specimens without capsular invasion. Increased expression was localized to the glandular cytoplasm, with tumor stroma yielding predominantly negative results. These findings provide additional evidence of the role of urokinase in determining the biologic behavior and metastatic potential of prostate cancer.

Chylothorax: a complication of a left subclavian vein thrombosis.

The development of a chylothorax is a rare complication of a superior vena caval thrombosis. We describe a unique case of chylous pleural effusion occurring in a patient with an underlying lymphoma who had a Hickman-Broviac catheter and a left subclavian vein thrombosis. The effusion resolved after the initiation anticoagulant therapy. This potentially reversible cause of a pleural effusion needs to be considered in any patient with a central venous catheter who is undergoing treatment for an otherwise malignant disorder.

Metoclopramide-induced sulfhemoglobinemia.

Metoclopramide, a drug with oxidant activity, has infrequently been reported to cause methemoglobinemia in infants. We present a unique case in which a patient on chronic metoclopramide therapy developed sulfhemoglobinemia that resolved with subsequent discontinuation of the drug. Mechanisms that may be important in the formation of sulfhemoglobin also are discussed.

Decreased fibrinolytic potential in patients with idiopathic avascular necrosis and transient osteoporosis of the hip.

A thrombotic etiology has been suggested as the cause of idiopathic avascular necrosis of the hip, although the underlying pathophysiological mechanisms are unknown. Transient osteoporosis of the hip has also been suggested to represent bone marrow edema that may be related to ischemia. We evaluated four patients with idiopathic avascular necrosis and one patient with transient osteoporosis of the hip for thrombotic potential placing a special emphasis on the fibrinolytic system. All five patients had identifiable abnormalities of fibrinolysis. Four patients had elevated levels of plasminogen activator inhibitor (PAI-1) and one patient had an inadequate increase in tissue plasminogen activator (tPA) post venous occlusion. Serum triglycerides were increased in three of the patients. These findings suggest an association between decreased fibrinolytic potential and the subsequent development of avascular necrosis and transient osteoporosis of the hip. These patients should have an evaluation of the fibrinolytic system with tPA and PAI-1 levels as well as a lipid profile.

p53 expression in incidental prostatic cancer.

Incidental prostate cancer is an indolent disease typically characterized by a benign clinical course. This is not clearly established, however, as recent reports suggest that up to 27% of cases progress with long-term follow-up. The indolent history of this disease led initially to the hypothesis that mutations of the p53 gene would be an infrequent event in this patient population. Archival specimens from 24 patients with Stage A1 carcinomas were evaluated for abnormal p53 expression. In 23 patients the disease was diagnosed after transurethral resection for bladder outlet obstructive symptoms, and in one patient after a radical prostatectomy. Using a monoclonal antibody (PAb 240) and an immunohistochemical technique, a total of 36 microfoci of tumor were evaluated. Thirteen (36%) microfoci were positive with an intense nuclear staining pattern (2+), and eight (22%) microfoci had an intermediate staining pattern. Four areas of prostatic intraepithelial neoplasia also stained positively with a 2+ staining pattern. These results suggest that abnormal p53 expression is a feature of a significant number of incidental prostatic carcinomas and that this occurrence is an early event in the development of the malignant phenotype.

Mutant p53 expression in prostate carcinoma.

The expression of the mutant p53 tumor suppressor gene was evaluated in 33 human prostate carcinomas. Using an immunohistochemical method with monoclonal antibodies PAb 1801 and PAb 240, 26 (79%) tumors demonstrated positive immunostaining for mutant p53. Only areas of glandular tumor were positive, with adjacent stromal elements and areas of glandular hyperplasia being negative. The predominant staining pattern was cytoplasmic. This pattern may be related to p53 binding to certain heat shock proteins (HSP 72/73), as a monoclonal antibody to these proteins demonstrated a cytoplasmic location as well. These results demonstrate that abnormal p53 expression is a frequent event in prostate cancer.

Takayasu arteritis presenting as retinal and vertebrobasilar ischemia.

A young woman presented with a 4-month history of retinal and vertebrobasilar ischemia. Angiography demonstrated narrowing of major branches of the aortic arch. Intractable, severe retroorbital pain of the right eye developed after a middle cerebral artery stroke. During 4 weeks of aggressive immunosuppressive therapy including IV high dose bolus corticosteroids and pulse cyclophosphamide, her neurologic deficit improved transiently, but her retroorbital pain persisted. She died of staphylococcal sepsis and pneumonia. An autopsy demonstrated thrombotic or fibrous occlusion, with minimal inflammation, of extracranial arteries.