Raheela Khan

Potassium channels in the human myometrium.

The contractility of the human uterus is under the fine control of a variety of interacting bioactive agents. During labour, the excitability of the uterus is drastically transformed in comparison with the non‐labour state and is manifest at the membrane level via the acivity of uterine ion channels. This article reviews the contribution of potassium (K+) channels to human uterine excitability.

A pre-operative elevated neutrophil: lymphocyte ratio does not predict survival from oesophageal cancer resection

BackgroundElevated pre-operative neutrophil: lymphocyte ratio (NLR) has been identified as a predictor of survival in patients with hepatocellular and colorectal cancer. The aim of this study was to examine the prognostic value of an elevated preoperative NLR following resection for oesophageal cancer.MethodsPatients who underwent resection for oesophageal carcinoma from June 1997 to September 2007 were identified from a local cancer database. Data on demographics, conventional prognostic markers, laboratory analyses including blood count results, and histopathology were collected and analysed.ResultsA total of 294 patients were identified with a median age at diagnosis of 65.2 (IQR 59-72) years. The median pre-operative time of blood sample collection was three days (IQR 1-8). The median neutrophil count was 64.2 × 10-9/litre, median lymphocyte count 23.9 × 10-9/litre, whilst the NLR was 2.69 (IQR 1.95-4.02). NLR did not prove to be a significant predictor of number of involved lymph nodes (Cox regression, p = 0.754), disease recurrence (p = 0.288) or death (Cox regression, p = 0.374). Furthermore, survival time was not significantly different between patients with high (≥ 3.5) or low (< 3.5) NLR (p = 0.49).ConclusionPreoperative NLR does not appear to offer useful predictive ability for outcome, disease-free and overall survival following oesophageal cancer resection.

The effects of potassium channel openers on isolated pregnant human myometrium before and after the onset of labor: Potential for tocolysis

OBJECTIVE Our purpose was to investigate the effects and pharmacologic properties of potassium channel openers in isolated pregnant human myometrium. STUDY DESIGN Biopsy specimens of myometrium obtained from 67 women during pregnancy and labor were used for isometric recording under physiologic conditions. RESULTS Levcromakalim and pinacidil, two prototype potassium channel openers, are potent inhibitors of spontaneous and induced (0.5 nmol/L oxytocin and 10 mumol/L phenylephrine) contractions in isolated human pregnant myometrium, obtained before and after the onset of labor. The sulfonylurea glibenclamide is an apparent competitive antagonist of this inhibition. No antagonism was observed with the sulfonylurea tolbutamide. Both potassium channel openers significantly inhibited contractility evoked by low (10 and 20 mmol/L) but not high (40 and 80 mmol/L) concentrations of extracellular potassium chloride. CONCLUSION These findings suggest that the relaxant ability of levcromakalim and pinacidil in human pregnant myometrium is because of potassium channel activation. This introduces a potential new approach for tocolysis.

Eag and HERG potassium channels as novel therapeutic targets in cancer

Voltage gated potassium channels have been extensively studied in relation to cancer. In this review, we will focus on the role of two potassium channels, Ether à-go-go (Eag), Human ether à-go-go related gene (HERG), in cancer and their potential therapeutic utility in the treatment of cancer. Eag and HERG are expressed in cancers of various organs and have been implicated in cell cycle progression and proliferation of cancer cells. Inhibition of these channels has been shown to reduce proliferation both in vitro and vivo studies identifying potassium channel modulators as putative inhibitors of tumour progression. Eag channels in view of their restricted expression in normal tissue may emerge as novel tumour biomarkers.

Down-Regulation of the α- and β-Subunits of the Calcium-Activated Potassium Channel in Human Myometrium with Parturition

Abstract Large-conductance, calcium-dependent potassium (BKCa) channels are implicated in maintaining uterine quiescence during pregnancy. The mechanisms whereby calcium sensitivity of the BKCa channel is dramatically removed at parturition remain unknown. The aim of the present study was to investigate whether this loss of calcium sensitivity of the BKCa channel with the onset of labor is associated with changes in the protein expression of the α- and/or β-subunit or arises from a physical dissociation of the α-subunit from the β-subunit. The β-subunit is a key determinant of BKCa-channel Ca2+ sensitivity. Western blot analysis, using α- and β-subunit-specific antibodies, detected bands of 110–125 and 36 kDa, respectively. Protein expression levels of the α-subunit in term labor myometrium were significantly reduced compared with term pregnancy without labor. Furthermore, α-subunit levels at term pregnancy were significantly increased relative to the nonpregnant state, whereas levels at preterm gestations were unchanged. Densitometric analysis demonstrated significantly decreased β-subunit levels in term and preterm labor samples compared with term nonlabor samples. Immunoprecipitation studies revealed the presence of both the α- and β-subunits in samples taken before or after the onset of labor. We conclude that during labor, the α-subunit is not physically uncoupled from the β-subunit, but a decline occurs in the level of β-subunit protein, which may underlie the loss of calcium and voltage sensitivity of the BKCa channel with labor. Furthermore, reduced β-subunit protein in preterm labor myometrium implies that ion channels may also contribute to pathophysiological labor.

Activation of large-conductance potassium channels in pregnant human myometrium by pinacidil

OBJECTIVE The aim was to investigate the effects of the potassium-channel opener pinacidil on single uterine potassium channels and the contribution of the latter to pinacidil-induced myometrial relaxation. STUDY DESIGN Myometrial strips and freshly dispersed uterine myocytes were prepared from the myometrial biopsy samples of women undergoing elective, nonlabor caesarean section at term gestation. RESULTS In isometric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the half maximal response of 0.4 +/- 0.1 micromol/L. This effect was antagonized by 500 nmol/L charybdotoxin. Application of 10 micromol/L glibenclamide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 micromol/L) produced a biphasic curve, which was fitted to a two-site model with values for agonist concentration yielding the half maximal response of 0.6 +/- 0.2 micromol/L and 189.7 +/- 0.8 micromol/L. Large-conductance calcium-dependent potassium channel activity was dramatically increased after application of pinacidil (between 10 and 100 micromol/L) to both inside-out and outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but not glibenclamide blocked pinacidil-induced unitary large-conductance calcium-dependent potassium channel activity. CONCLUSION Pinacidil-mediated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-dependent potassium channels in addition to adenosine triphosphate potassium channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytics in the treatment of preterm labor.

The Eag potassium channel as a new prognostic marker in ovarian cancer.

BackgroundOvarian cancer is the second most common cancer of the female genital tract in the United Kingdom (UK), accounting for 6% of female deaths due to cancer. This cancer is associated with poor survival and there is a need for new treatments in addition to existing chemotherapy to improve survival. Potassium (K+) channels have been shown to be overexpressed in various cancers where they appear to play a role in cell proliferation and progression.ObjectivesTo determine the expression of the potassium channels Eag and HERG in ovarian cancer tissue and to assess their role in cell proliferation.MethodsThe expression of Eag and HERG potassium channels was examined in an ovarian cancer tissue microarray. Their role in cell proliferation was investigated by blocking voltage-gated potassium channels in an ovarian cancer cell line (SK-OV-3).ResultsWe show for the first time that high expression of Eag channels in ovarian cancer patients is significantly associated with poor survival (P = 0.016) unlike HERG channel expression where there was no correlation with survival. There was also a significant association of Eag staining with high tumour grade (P = 0.014) and presence of residual disease (P = 0.011). Proliferation of SK-OV-3 cells was significantly (P < 0.001) inhibited after treatment with voltage gated K+ channel blockers.ConclusionThis novel finding demonstrates a role for Eag as a prognostic marker for survival in patients with ovarian cancer.

The effects of a progesterone metabolite, 5β‐dihydroprogesterone, on oxytocin receptor binding in human myometrial membranes

Objective To determine the effect of the progesterone metabolite 5β‐dihydroprogesterone on human oxytocin receptor binding in myometrial membranes and on whole‐cell calcium current in single myometrial cells.

The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line

BackgroundThe voltage gated potassium (K+) channels Eag and HERG have been implicated in the pathogenesis of various cancers, through association with cell cycle changes and programmed cell death. The role of these channels in the onset and progression of ovarian cancer is unknown. An understanding of mechanism by which Eag and HERG channels affect cell proliferation in ovarian cancer cells is required and therefore we investigated their role in cell proliferation and their effect on the cell cycle and apoptosis of ovarian cancer cells.MethodsThe presence of Eag and HERG was determined in SK-OV-3 cells using immunofluorescence and western blotting. The effect of the Eag blockers (imipramine and clofilium) and HERG blockers (E-4031 and ergtoxin) on cell proliferation was assessed using the MTS assay with further investigation of their role in the cell cycle and apoptosis determined by flow cytometry.ResultsEag and HERG channels were present in the cytoplasm and nuclei of SK-OV-3 cells. There was significant inhibition of proliferation of SK-OV-3 cells by imipramine (P < 0.001) and ergtoxin (P < 0.05) at 72 hours of culture. Incubation of cells with ergtoxin led to the accumulation of cells in the S and G2/M phase, while cells accumulated in S phase after incubation with E-4031, with no effect on apoptosis. Imipramine did not affect the cell cycle but increased the proportion of SK-OV-3 cells undergoing early apoptosis.ConclusionBoth Eag and HERG channels are expressed in SK-OV-3 ovarian cancer cells and have a role in cell proliferation. HERG channels affect the cell cycle while Eag channels are implicated in the inhibition of apoptosis of ovarian cancer cells. The family of Eag channels may represent a new therapeutic target for the treatment of ovarian cancer.

Probing the link between oestrogen receptors and oesophageal cancer

BackgroundHuman oesophageal carcinoma is considered to be one of the most aggressive malignancies and has a very poor prognosis. The incidence of oesophageal cancer shows a gender bias and is higher in males compared with females, the ratio between males and females varying from 3:1 to 7:1. This sex ratio is not entirely attributable to differences in the prevalence of known risk factors between the sexes. The potential role of oestrogen receptors (ER) in oesophageal cancer has been debated for several years but the significance of the receptors in this cancer remains unknown. Most of the work has been based on immunohistochemistry and has not been validated with other available techniques. The inconsistencies in the published literature on the link between ER expression and oesophageal cancer warrant a thorough evaluation of the potential role of ERs in this malignancy. Even the expression of the two ER isoforms, ERα and ERβ, and its implications for outcome of treatments in histological subtypes of oesophageal tumours is ill defined. The aim of this article is to provide updated information from the available literature on the current status of ER expression in oesophageal cancer and to discuss its potential therapeutic role.Methods and ResultsWe performed a comprehensive literature search and analysed the results regarding ER expression in oesophageal tumours with special emphasis on expression of different oestrogen receptors and the role of sex hormones in oesophageal cancer. This article also focuses on the significance of the two main ER subtypes and mechanisms underlying the presumed male predominance of this disease.ConclusionWe postulate that differential oestrogen receptor status may be considered a biomarker of poor clinical outcome based on tissue dedifferentiation or advanced stage of the disease. Further, if we can establish the importance of oestrogen and its receptors in the context of oesophageal cancer, then this may lead to a new future direction in the management of this malignancy.