Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells

<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 (<it>PLK1</it>) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy.</p> <p>Methods</p> <p>We examined the expression of <it>PLK1 </it>mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting <it>PLK1 </it>mRNA on tumor-initiating cells was evaluated using tumor sphere assays.</p> <p>Results</p> <p>Analysis of gene expression in two independent cohorts revealed that <it>PLK1 </it>mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 (<it>SOX2</it>) mRNA in tumor spheres indicating a possible role in targeting tumor inititiating cells.</p> <p>Conclusions</p> <p>Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation.</p

Resistance training improves strength and functional measures in patients with end-stage renal disease.

BACKGROUND: The current study was designed to examine the effect of 12 weeks of resistance training on strength and functional ability in 10 medically stable hemodialysis patients (age, 42.8 4.4 years). METHODS: Subjects were tested on four separate occasions, each separated by 6 weeks. The first (T1) and second tests (T2) were controls with no exercise intervention between them. T3 followed 6 weeks of resistance training, and T4 occurred after 12 weeks of training. Variables tested included percentage of body fat, distance covered in the 6-minute walk test, peak torque of quadriceps muscles of the dominant leg, maximal handgrip strength, normal and maximal walking speeds, and time to complete 10 repetitions of the sit-to-stand-to-sit test. Data were analyzed by means of a one-way repeated-measures analysis of variance procedure. RESULTS: Results indicate that after 12 weeks of training, there was a significant (P \u3c 0.05) increase (12.7%) in peak torque at 90 degrees /s (139.1 19.3 nm) compared with T1 and T2 (mean, 124.1 18.7 [SEM]; 123.5 16.9 Nm), respectively. The distance covered during the 6-minute walk was increased ( approximately 5%; P \u3c 0.05) compared with baseline (T1, 522.1 46.2 m; 521.9 48.5 m) after 6 weeks of training (548.3 52.1 m) and remained elevated at week 12 (546.5 54.2 m). Maximal walking speed was increased (P \u3c 0.05) by week 12 (195.9 15.4 cm/s) compared with baseline (T1, 182.9 12.7; 185.5 13.0 cm/s). Time to complete 10 repetitions of the sit-to-stand-to-sit test decreased at 12 weeks (17.8 1.9 seconds) versus baseline (T1, 20.3 1.5 seconds; T2, 20.6 5.5 seconds). CONCLUSION: Resistance training can be used safely to increase strength and functional capacity in stable hemodialysis patients. Copyright 2002 by the National Kidney Foundation, Inc

Acute renal failure and hyperkalaemia associated with cyclooxygenase-2 inhibitors.

BACKGROUND: The renal effects of cyclooxygenase-2 (COX-2) inhibitors have been incompletely elucidated, and acute renal failure (ARF) due to COX-2 inhibitors has been reported. METHODS: In order to determine the causes of ARF and hyperkalaemia in five patients during COX-2 inhibitor therapy, we carefully analysed case studies of consecutive in-patients or out-patients referred to our Renal Division over a 6-month period for ARF and hyperkalaemia who had recently received COX-2 inhibitors. RESULTS: ARF developed 2-3 weeks after COX-2 inhibitor therapy in five patients. The ARF was consistent with pre-renal azotaemia from renal hypoperfusion. Four patients were receiving the loop diuretic, furosemide. Four patients developed hyperkalaemia and decreased serum bicarbonate despite diuretic therapy, and one patient had changes in plasma renin activity and aldosterone levels consistent with reversible hyporeninaemic hypoaldosteronism. Renal failure was reversible after discontinuation of diuretics and COX-2 inhibitors. CONCLUSIONS: COX-2 inhibitors may cause reversible ARF and hyperkalaemia in patients with oedematous conditions treated with low sodium diets and loop diuretics