Levamisole induced apoptosis in cultured vascular endothelial cells
Open Access
- 1 December 2000
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 131 (8), 1577-1583
- https://doi.org/10.1038/sj.bjp.0703660
Abstract
To better understand the anticancer activity of Levamisole (LMS), which serves as an adjuvant in colon cancer therapy in combination with 5‐Fluorouracil, this study analyses LMS' ability to induce apoptosis and growth arrest in cultured human micro‐ and macrovascular endothelial cells (ECs) and fibroblasts. Cells exposed (24 h) to Levamisole (range: 0.5–2 mmol l−1) alone or in combination with antioxidants (10 mmol l−1 glutathione or 5 mmol l−1 N‐Acetylcysteine or 0.1 mmol l−1 Tocopherol) were evaluated for apoptosis (3H‐thymidine assays, in situ staining), mRNA/protein expression (Northern/Western blot), and proliferation (3H‐thymidine incorporation). Levamisole dose‐dependently increased apoptosis in ECs to 230% (HUVECs‐human umbilical vein ECs), 525% (adult human venous ECs) and 600% (human uterine microvascular ECs) but not in fibroblasts compared to control cells (set as 100%). Levamisole increased in ECs integrin‐dependent matrix adhesion, inhibited proliferation (−70%), reduced expression of survival factors such as clusterin (−30%), endothelin‐1 (−43%), bcl‐2 (−34%), endothelial NO‐synthase (−32%) and pRb (Retinoblastoma protein: −89%), and increased that of growth arrest/death signals such as p21 (+73%) and bak (+50%). LMS (2 mmol l−1)‐induced apoptosis was inhibited by glutathione (−50%) and N‐Acetylcysteine (−36%), which also counteracted reduction by Levamisole of pRb expression, suggesting reactive oxygen species and pRb play a role in these processes. The ability of LMS to selectively induce apoptosis and growth arrest in endothelial cells potentially hints at vascular targeting to contribute to Levamisole's anticancer activity. British Journal of Pharmacology (2000) 131, 1577–1583; doi:10.1038/sj.bjp.0703660Keywords
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