A novel lipophilic amiloride derivative efficiently kills chemoresistant breast cancer cells.

Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer.

Structure-Activity Relationship Study Identifies a Novel Lipophilic Amiloride Derivative that Efficiently Kills Chemoresistant Breast Cancer Cells.

Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer.

Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis.

Background: In light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis.

Methods: Vangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice.

Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers.

Background: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood.

Objective: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers.

Design: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task.

Ethanol effects on local cerebral glucose utilization in high-alcohol-drinking and low-alcohol-drinking rats.

Divergent ethanol-drinking behavior in rats selectively bred for high- or low-ethanol-drinking behavior could be related to differences in the sensitivity of the CNS to ethanol. In the current study, we examined the effects of acute (i.e.

Local cerebral glucose utilization after relapse in ethanol drinking in alcohol-preferring (P) rats.

The [(14)C]-2-deoxyglucose ([(14)C]-2-DG) quantitative autoradiographic technique was used to determine rates of local cerebral glucose utilization (LCGU) in discrete brain regions of adult, male alcohol-preferring (P) rats after 2 weeks of ethanol deprivation (E-D), 3 and 14 days of ethanol-relapse drinking (E-R3; E-R14), and in P rats, which were chronically drinking ethanol (E-C) for 8 weeks during daily 3-h scheduled-access sessions to 15% (vol./vol.) ethanol and water, or were ethanol-naive (E-N).

PET imaging of differential cortical activation by monaural speech and nonspeech stimuli.

Positron emission tomography imaging was used to investigate the brain activation patterns of listeners presented monaurally (right ear) with speech and nonspeech stimuli. The major objectives were to identify regions involved with speech and nonspeech processing, and to develop a stimulus paradigm suitable for studies of cochlear-implant subjects. Scans were acquired under a silent condition and stimulus conditions that required listeners to press a response button to repeated words, sentences, time-reversed (TR) words, or TR sentences.

Alcohol-naïve alcohol-preferring (P) rats exhibit higher local cerebral glucose utilization than alcohol-nonpreferring (NP) and Wistar rats.

Background: The present study determined local cerebral glucose utilization (LCGU) rates in alcohol-naïve alcohol-preferring (P), alcohol nonpreferring (NP), and outbred Wistar rats to test the hypothesis that innate differences in functional neuronal activity are present in limbic regions as a result of selective breeding for high-alcohol drinking behavior.

Methods: All procedures were conducted during the dark cycle. 2-[14C]deoxyglucose ([14C]2-DG; 125 microCi/kg) was injected intravenously and timed arterial blood samples were collected during the following 45 min and assayed for glucose and [14C]2-DG content.

Long-term effects of alcohol drinking on cerebral glucose utilization in alcohol-preferring rats.

The 2-[14C]deoxyglucose (2-DG) quantitative autoradiography technique was used to determine rates of local cerebral glucose utilization (LCGU) in discrete brain regions in alcohol-chronic (A-C), alcohol-deprived (A-D) and alcohol-naïve (A-N) adult, male alcohol-preferring (P) rats. The hypothesis to be tested is that neuronal alterations occur as a result of chronic alcohol drinking and some of these alterations persist for long periods in the absence of alcohol. Following 6 weeks of daily 4-h scheduled access sessions to 15% (v/v) ethanol and water, group A-D received only water during the sessions over the next 2 weeks, whereas groups A-C and A-N continued to receive ethanol-water and water-water, respectively.

Quantitative autoradiography of mu-opioid receptors in the CNS of high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

Background: The binding of [3H]DAMGO to mu-opioid sites was measured in the CNS of selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats to test the hypothesis that high alcohol preference is associated with higher densities of mu-opioid receptors.

Methods: Adult, alcohol-naïve male HAD and LAD rats from replicate line 1 were decapitated and their brains frozen in isopentane. Brain sections were incubated with 5 nM [3H]DAMGO, and nonspecific binding was determined in the presence of unlabeled DAMGO.

Local cerebral glucose utilization rates in alcohol-naïve high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats.

Background: The present study compared baseline local cerebral glucose utilization (LCGU) values within reward-relevant brain regions in alcohol-naïve, adult male high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats from replicate lines 1 and 2.

Methods: 2-[14C]Deoxyglucose ([14C]2-DG) was injected (125 microCi/kg) intravenously during the rats' dark cycle. Timed arterial blood samples were collected over 45 min and assayed for glucose as well as [14C]2-DG content.