The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism

BACKGROUND: By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. METHODS: Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. RESULTS: Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. CONCLUSION: We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132

GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycansA review

Aims Glycosaminoglycan (GAG) layer replenishment is a cornerstone in the therapy of interstitial cystitis (IC). During the last years intravesical GAG layer replenishment has proven to be an effective treatment for overactive bladder (OAB), radiation cystitis, and recurrent urinary tract infections (UTIs). Methods Examination of different substances available for intravesical GAG replenishment and evaluation of the evidence for the treatment of the above-mentioned conditions. Results We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE) database for studies on intravesical GAG replenishment. A total of 27 clinical studies remain relevant to this topic, many of them with mixed patient selection and suboptimal definition of symptom improvement/success. Two placebo controlled studies with hyaluronic acid failed to show superiority and have not been published. One active controlled randomized study has been published showing that chondroitin sulphate 0.2% has a clear benefit for OAB patients. Another study with chondroitin sulphate 2.0% failed to show statistically significant evidence, but was underpowered. Conclusions A short number of randomized controlled studies confirm efficacy of intravesical GAG layer replenishment therapy. Concluded from the study background (which comprises also uncontrolled studies), so far chondroitin sulphate 0.2% is in favor for intravesical GAG layer replenishment therapy. In general, large-scale trials are urgently needed to underline the benefit of this type of therapy. Neurourol. Urodynam. 32: 918, 2013

GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycansA review

Aims Glycosaminoglycan (GAG) layer replenishment is a cornerstone in the therapy of interstitial cystitis (IC). During the last years intravesical GAG layer replenishment has proven to be an effective treatment for overactive bladder (OAB), radiation cystitis, and recurrent urinary tract infections (UTIs). Methods Examination of different substances available for intravesical GAG replenishment and evaluation of the evidence for the treatment of the above-mentioned conditions. Results We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE) database for studies on intravesical GAG replenishment. A total of 27 clinical studies remain relevant to this topic, many of them with mixed patient selection and suboptimal definition of symptom improvement/success. Two placebo controlled studies with hyaluronic acid failed to show superiority and have not been published. One active controlled randomized study has been published showing that chondroitin sulphate 0.2% has a clear benefit for OAB patients. Another study with chondroitin sulphate 2.0% failed to show statistically significant evidence, but was underpowered. Conclusions A short number of randomized controlled studies confirm efficacy of intravesical GAG layer replenishment therapy. Concluded from the study background (which comprises also uncontrolled studies), so far chondroitin sulphate 0.2% is in favor for intravesical GAG layer replenishment therapy. In general, large-scale trials are urgently needed to underline the benefit of this type of therapy. Neurourol. Urodynam. 32: 918, 2013

The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism.

BackgroundBy modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition.MethodsProstate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay.ResultsInhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity.ConclusionWe conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132

The 2013 EAU Guidelines on Chronic Pelvic Pain:Is Management of Chronic Pelvic Pain a Habit, a Philosophy, or a Science? 10 Years of Development

<p>Context: Progress in the science of pain has led pain specialists to move away from an organ-centred understanding of pain located in the pelvis to an understanding based on the mechanism of pain and integrating, as far as possible, psychological, social, and sexual dimensions of the problem. This change is reflected in all areas, from taxonomy through treatment. However, deciding what is adequate investigation to rule out treatable disease before moving to this way of engaging with the patient experiencing pain is a complex process, informed by pain expertise as much as by organ-based medical knowledge.</p><p>Objective: To summarise the evolving changes in the management of patients with chronic pelvic pain by referring to the 2012 version of the European Association of Urology (EAU) guidelines on chronic pelvic pain.</p><p>Evidence acquisition: The working panel highlights some of the most important aspects of the management of patients with chronic pelvic pain emerging in recent years in the context of the EAU guidelines on chronic pelvic pain. The guidelines were completely updated in 2012 based on a systematic review of the literature from online databases from 1995 to 2011. According to this review, levels of evidence and grades of recommendation were added to the text. A full version of the guidelines is available at the EAU office or Web site (www.uroweb.org).</p><p>Evidence synthesis: The previously mentioned issues are explored in this paper, which refers throughout to dilemmas for the physician and treatment team as well as to the need to inform and engage the patient in a collaborative empirical approach to pain relief and rehabilitation. These issues are exemplified in two case histories.</p><p>Conclusions: Chronic pelvic pain persisting after appropriate treatment requires a different approach focussing on pain. This approach integrates the medical, psychosocial, and sexual elements of care to engage the patient in a collaborative journey towards self-management. (C) 2013 European Association of Urology. Published by Elsevier B. V. All rights reserved.</p>