Epigallocatechin‐3‐gallate induces mesothelioma cell death via H2O2−dependent T‐type Ca2+ channel opening

Journal of Cellular and Molecular Medicine

Elia Ranzato²  Simona Martinotti²  Valeria Magnelli²  Bruno Murer¹  Stefano Biffo²  Luciano Mutti³ 

[1] Department of Anatomic Pathology, Dell'Angelo Hospital, Zelarino, Italy;Dipartimento di Scienze e Innovazione Tecnologica, DiSIT, University of Piemonte Orientale “Amedeo Avogadro”, Alessandria, Italy;Dept General Medicine, Lab of Clinical Oncology, Vercelli National Health Trust, Vercelli, Italy

关键词: anticancer therapy;    hydrogen peroxide;    reactive oxygen species;    malignant mesothelioma;    T‐type calcium channels;   

DOI  :  10.1111/j.1582-4934.2012.01584.x

来源: Wiley

【 摘 要 】

Abstract

Malignant mesothelioma (MMe) is a highly aggressive, lethal tumour requiring the development of more effective therapies. The green tea polyphenol epigallocathechin-3-gallate (EGCG) inhibits the growth of many types of cancer cells. We found that EGCG is selectively cytotoxic to MMe cells with respect to normal mesothelial cells. MMe cell viability was inhibited by predominant induction of apoptosis at lower doses and necrosis at higher doses. EGCG elicited H₂O₂ release in cell cultures, and exogenous catalase (CAT) abrogated EGCG-induced cytotoxicity, apoptosis and necrosis. Confocal imaging of fluo 3-loaded, EGCG-exposed MMe cells showed significant [Ca²⁺]_i rise, prevented by CAT, dithiothreitol or the T-type Ca²⁺ channel blockers mibefradil and NiCl₂. Cell loading with dihydrorhodamine 123 revealed EGCG-induced ROS production, prevented by CAT, mibefradil or the Ca²⁺ chelator BAPTA-AM. Direct exposure of cells to H₂O₂ produced similar effects on Ca²⁺ and ROS, and these effects were prevented by the same inhibitors. Sensitivity of REN cells to EGCG was correlated with higher expression of Ca_v3.2 T-type Ca²⁺ channels in these cells, compared to normal mesothelium. Also, Ca_v3.2 siRNA on MMe cells reduced in vitro EGCG cytotoxicity and abated apoptosis and necrosis. Intriguingly, Ca_v3.2 expression was observed in malignant pleural mesothelioma biopsies from patients, but not in normal pleura. In conclusion, data showed the expression of T-type Ca²⁺ channels in MMe tissue and their role in EGCG selective cytotoxicity to MMe cells, suggesting the possible use of these channels as a novel MMe pharmacological target.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd