Altering bioelectricity on inhibition of human breast cancer cells

Background: Membrane depolarization is associated with breast cancer. Depolarization-activated voltage-gated ion channels are directly implicated in the initiation, proliferation, and metastasis of breast cancer. Methods: In this study, the role of voltage-gated potassium and calcium ion channel modulation was explored in two different invasive ductal human carcinoma cell lines, MDA-MB-231 (triple-negative) and MCF7 (estrogen-receptor-positive). Results: Resting membrane potential is more depolarized in MCF7 and MDA-MB-231 cells compared to normal human mammary epithelial cells. Increasing extracellular potassium concentration up to 50 mM depolarized mem‑ brane potential and greatly increased cell growth. Tetraethylammonium (TEA), a non-specific blocker of voltagegated potassium channels, stimulated growth of MCF7 cells (control group grew by 201 %, 1 mM TEA group grew 376 %). Depolarization-induced calcium influx was hypothesized as a requirement for growth of human breast cancer. Removing calcium from culture medium stopped growth of MDA and MCF7 cells, leading to cell death after 1 week. Verapamil, a blocker of voltage-gated calcium channels clinically used in treating hypertension and coronary disease, inhibited growth of MDA cells at low concentration (10–20 μM) by 73 and 92 % after 1 and 2 days, respectively. At high concentration (100 μM), verapamil killed \u3e90 % of MDA and MCF7 cells after 1 day. Immunoblotting experiments demonstrated that an increased expression of caspase-3, critical in apoptosis signaling, positively correlated with verapamil concentration in MDA cells. In MCF7, caspase-9 expression is increased in response to verapamil. Conclusions: Our results support our hypotheses that membrane depolarization and depolarization-induced calcium influx stimulate proliferation of human breast cancer cells, independently of cancer subtypes. The underlying mechanism of verapamil-induced cell death involves different caspases in MCF7 and MDA-MB-231. These data sug‑ gest that voltage-gated potassium and calcium channels may be putative targets for pharmaceutical remediation in human invasive ductal carcinomas

Clinical, angiographic, and intravascular ultrasound characteristics of early saphenous vein graft failure

AbstractObjectivesWe sought to examine saphenous vein graft (SVG) lesions that fail within the first year after operation.BackgroundSaphenous vein grafts remain patent for approximately 10 years; however, up to 15% to 20% of SVGs become occluded within the first year.MethodsWe studied 100 patients who underwent percutaneous coronary intervention (PCI) for early (<1 year post-implantation) SVG failure lesions and compared them with a diabetes- and hypercholesterolemia-matched cohort of late SVG failures (>1 year). Coronary angiography and intravascular ultrasound images were analyzed.ResultsThe majority of patients in both groups were males who presented with unstable angina; 36% were diabetic. Graft ages were 6.0 ± 2.9 months and 105.4 ± 50.8 months, respectively. The early SVG failure lesion location was more often ostial or proximal (62% vs. 42%, respectively). Early SVG failures were angiographically smaller than late failures (reference: 2.47 ± 0.86 mm vs. 3.26 ± 0.83 mm, p < 0.001) but had similar lesion lengths. Intravascular ultrasound showed that early failure lesions had smaller proximal and distal reference lumen areas (7.3 ± 6.8 mm2vs. 10.6 ± 3.8 mm2, p = 0.026) and greater reference plaque burden than late failures (52.3% vs. 36.1%, p < 0.001). After PCI, 20.6% of early and 30.6% of late failure lesions had creatine kinase-myocardial band (CK-MB) greater than twice normal.ConclusionsEarly SVG failure is mostly proximal or ostial, lesions appear focal, and early SVGs appear smaller than late SVGs. Intravascular ultrasound shows significant reference segment plaque burden, suggesting more severe, diffuse SVG disease