Publications by authors named "Shea Hatcher"

4 Publications

  • Page 1 of 1

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene.

Transl Oncol 2020 Jun 11;13(6):100775. Epub 2020 May 11.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, 400 Lee Street North, Lewisburg, WV. Electronic address:

Breast cancer patients presenting with symptomatic brain metastases have poor prognosis, and current chemotherapeutic agents are largely ineffective. In this study, we evaluated the hypomethylating agent azacitidine (AZA) for its potential as a novel therapeutic in preclinical models of brain metastasis of breast cancer. We used the parental triple-negative breast cancer MDA-MB-231 (231) cells and their brain colonizing counterpart (231Br) to ascertain phenotypic differences in response to AZA. We observed that 231Br cells have higher metastatic potential compared to 231 cells. With regard to therapeutic value, the AZA IC value in 231Br cells is significantly lower than that in parental cells (P < .01). AZA treatment increased apoptosis and inhibited the Wnt signaling transduction pathway, angiogenesis, and cell metastatic capacity to a significantly higher extent in the 231Br line. AZA treatment in mice with experimental brain metastases significantly reduced tumor burden (P = .0112) and increased survival (P = .0026) compared to vehicle. Lastly, we observed a decreased expression of keratin 18 (an epithelial maker) in 231Br cells due to hypermethylation, elucidating a potential mechanism of action of AZA in treating brain metastases from breast cancer.
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http://dx.doi.org/10.1016/j.tranon.2020.100775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225776PMC
June 2020

Susceptibility to ischemia-induced ventricular fibrillation in isolated female rat hearts varies moderately with estrous cycle stage.

J Pharmacol Toxicol Methods 2013 May-Jun;67(3):134-9. Epub 2013 Jan 26.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, 400 N Lee Street, Lewisburg, WV 24901, USA.

Introduction: The vast majority of studies employing the isolated perfused rat heart model to study ischemic arrhythmias have used male rats only. The objective of this study was to determine the susceptibility to ischemia-induced ventricular fibrillation (VF) in isolated female rat hearts in each stage of the estrous cycle that corresponds with a different endogenous reproductive hormonal environment.

Methods: Hearts were isolated from female rats under pentobarbital anesthesia and perfused with modified Krebs solution containing 3mM K(+). Experiments were grouped according to estrous cycle stage that was determined by prior vaginal lavage (n=10-13 per group). A group of male rat hearts was used as the control. Regional ischemia was induced by coronary ligation and maintained for 30min. The incidence of VF was determined from the ECG.

Results: The incidence of VF in male hearts was 100%, while the incidence of VF in female hearts was also high but varied moderately with stage of the estrous cycle (diestrus 70%, metestrus 100%, proestrus 90%, estrus 69%; P>0.05). Compared to male hearts, the onset of VF was similar in all groups except for hearts excised from rats in proestrus, in which it was delayed. There was no difference between groups in an arrhythmia score, ischemic zone size, or baseline electrocardiographic or hemodynamic variables.

Discussion: In conclusion, the susceptibility of isolated female rat hearts to ischemic VF is comparable to that of male rat hearts, meaning that isolated female rat hearts can be used as controls in studies to assess antiarrhythmic drug efficacy. Since female rats can be used for isolated heart studies of ischemic VF, the need to cull female rats is reduced. However, the variation in VF susceptibility in female rat hearts that is associated with the different stages of the estrous cycle may affect statistical power that could potentially lead to Type II statistical errors. This problem can be prevented with careful randomization.
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http://dx.doi.org/10.1016/j.vascn.2013.01.008DOI Listing
March 2014

Mitochondrial uncoupling agents trigger ventricular fibrillation in isolated rat hearts.

J Cardiovasc Pharmacol 2011 Apr;57(4):439-46

West Virginia School of Osteopathic Medicine, Lewisburg, WV 24901, USA.

Sudden cardiac death resulting from ventricular fibrillation (VF) remains a major cause of mortality. The purpose of this study was to investigate the roles of loss of oxidative phosphorylation and activation of the mitochondrial ATP-sensitive K+ channel and permeability transition pore in VF development during myocardial ischemia by using mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenylhydrazone and 2,4-dinitrophenol) and channel blockers (5-hydroxydecanoate and cyclosporine A) at concentrations that have been demonstrated to block the intended targets selectively. Isolated rat hearts (n = 8 per group) were perfused with 0.3 μM carbonyl cyanide m-chlorophenylhydrazone, 100 μM 2,4-dinitrophenol, 0.2 μM cyclosporine A, 100 μM 5-hydroxydecanoate, or vehicle solution and regional ischemia induced after 10 minutes. Carbonyl cyanide m-chlorophenylhydrazone and 2,4 dinitrophenol caused profound QT shortening and triggered VF in 100% of hearts before ischemia. During ischemia, neither cyclosporine A (88%) nor 5-hydroxydecanoate (100%) reduced VF incidence compared with control (100% VF). In separate hearts, carbonyl cyanide m-chlorophenylhydrazone decreased tissue ATP content, and glibenclamide or glimepiride delayed the QT shortening and onset of VF triggered by carbonyl cyanide m-chlorophenylhydrazone. In conclusion, mitochondrial uncoupling agents trigger VF, likely as a result of ATP depletion with subsequent activation of sarcolemmal ATP-sensitive K+ currents. The mechanism of VF in ischemia does not involve activation of the mitochondrial ATP-sensitive K+ channel or permeability transition pore.
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http://dx.doi.org/10.1097/FJC.0b013e31820d5342DOI Listing
April 2011

Reduced antiarrhythmic efficacy of verapamil in isolated rat hearts in the presence of elevated extracellular calcium.

J Cardiovasc Pharmacol 2011 Apr;57(4):455-62

West Virginia School of Osteopathic Medicine, Lewisburg, WV 24901, USA.

An isolated heart method that has been proposed to aid in ascertaining the involvement of L-type calcium channel blockade in the mechanism of action of novel antiarrhythmic drugs involves increasing the calcium concentration in the perfusion buffer. The purpose of this study was to determine the validity of this method using an established L-type calcium channel blocker, verapamil. Isolated rat hearts were perfused with normal calcium (1.4 mM) Krebs solution containing drug vehicle only, a normal calcium solution containing verapamil (300 nM), or a high calcium (2.8 mM) solution containing verapamil. The occurrence of ventricular fibrillation during a subsequent period of regional myocardial ischemia was monitored. The incidence of ventricular fibrillation was significantly reduced from 80% in controls to 20% by perfusion with verapamil in normal calcium Krebs solution (P < 0.05). Perfusion with the high calcium solution increased the incidence of ventricular fibrillation in the presence of verapamil to 40% (P > 0.05 versus controls). We conclude that the antiarrhythmic effect of verapamil in isolated hearts can be attenuated by increasing the calcium content of the perfusion solution, but a twofold increase in the calcium concentration failed to fully restore susceptibility to ventricular fibrillation to that observed in verapamil-free controls.
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http://dx.doi.org/10.1097/FJC.0b013e31820ff60eDOI Listing
April 2011