Sorafenib is a multikinase inhibitor that induces apoptosis in human leukemia and other malignant cells.Recently, we demonstrated that sorafenib diminishes Mcl-1 protein expression by inhibiting translation through a MEK1/2-ERK1/2 signaling-independent mechanism and that this phenomenon plays a key functional role in sorafenib-mediated lethality. Here, we report that inducible expression of constitutively active MEK1 fails to protect cells from sorafenib-mediated lethality, indicating that sorafenib-induced cell death is unrelated to MEK1/2-ERK1/2 pathway inactivation. Notably, treatment with sorafenib induced endoplasmic reticulum (ER) stress in human leukemia cells (U937) manifested by immediate cytosolic-calcium mobilization, GADD153 and GADD34 protein induction, PKR-like ER kinase (PERK) and eukaryotic initiation factor 2␣ (eIF2␣) phosphorylation, XBP1 splicing, and a general reduction in protein synthesis as assessed by [35 S]methionine incorporation. These events were accompanied by pronounced generation of reactive oxygen species through a mechanism dependent upon cytosolic-calcium mobilization and a significant decline in GRP78/Bip protein levels. Interestingly, enforced expression of IRE1␣ markedly reduced sorafenib-mediated apoptosis, whereas knockdown of IRE1␣ or XBP1, disruption of PERK activity, or inhibition of eIF2␣ phosphorylation enhanced sorafenib-mediated lethality. Finally, downregulation of caspase-2 or caspase-4 by small interfering RNA significantly diminished apoptosis induced by sorafenib. Together, these findings demonstrate that ER stress represents a central component of a MEK1/2-ERK1/2-independent cell death program triggered by sorafenib.The discovery that aberrant activation of the Ras-Raf-MEK1/2-ERK1/2 module occurs in a high percentage (30%) of human cancers (12, 42, 48, 57) provided a rationale for attempting to disrupt this pathway as a candidate anticancer strategy. Recently, a number of specific inhibitors designed to interrupt this pathway at the level of Ras, Raf, or MEK1/2 have been developed. Among these, sorafenib, a biaryl urea, also known as BAY 43-9006 or Nexavar, was initially developed as a specific inhibitor of C-Raf and B-Raf. However, subsequent studies revealed that it also inhibits several other tyrosine kinases involved in tumor progression, including VEGFR-2, VEGFR-3, PDGFR-␤, Flt3, c-Kit, and Ret (6, 60). Interestingly, sorafenib has been shown to inhibit mutant (V600E) B-Raf kinase activities in vitro and to diminish MEK/extracellular signal-regulated kinase (ERK) activation in various tumor cell lines, including those harboring mutant Ras or B-Raf (25,56,60). Although this compound has potent activity in preclinical tumor xenograft models against a variety of tumor cell types (60), has shown promising activity in a number of clinical trials, and has recently been approved for the treatment of advanced renal cell carcinoma (51), the mechanism(s) by which it exerts its antitumor activity has not been fully elucidated and is currently the subject of ongoing i...

Mechanisms underlying apoptosis induced by concomitant interruption of the mitogen-activated protein kinase kinase/ extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways were investigated in human leukemia cells. Inhibition of these pathways using the MEK inhibitor PD184352 or U0126 and the PI3K/ Akt inhibitor perifosine strikingly induced apoptosis in multiple malignant human hematopoietic cells, and substantially reduced the colony-forming capacity of primary acute myeloblastic leukemia, but not normal CD34 ؉ cells. These events

This study demonstrates that human detrusor smooth muscle displays both length adaptation and Tap . Furthermore, Tap may be regulatable through a rho-kinase pathway. These biomechanical processes may be important in the pathophysiology of both overactive bladder and detrusor underactivity. Neurourol. Urodynam. 35:792-797, 2016. © 2015 Wiley Periodicals, Inc.

Fast Fourier transform analysis revealed that rabbit low amplitude rhythmic contractions consist of a basal tonic component plus 2 phasic components. The amplitude of all 3 components was length dependent. The frequency of the fast component was not length dependent and the slow component was absent at short muscle lengths, developing only at muscle lengths beyond that producing a maximum active contraction.

TVT-O placement is associated with cure/improvement of U and UUI in a significant proportion of patients with mixed urinary incontinence. Further, the observed improvements in U/UUI persist at 12 months and appear to have a durable positive association with QOL.