Received for publication January 23, 2007.
Revised February 26, 2007.
Accepted for publication February 26, 2007.

Mechanism of thiazolidinedione-dependent cell death in Jurkat T cells

Abstract

Thiazolidinediones are synthetic agonists for the transcriptionfactor peroxisome proliferator-activated receptor (PPAR) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects like induction of cell death by thiazolidinediones deserve consideration. Although PPAR-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPAR-independent cell demise. In Jurkat T cells ciglitazone and troglitazone provoked rapid and dose- dependent cell death, while rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone whereas ciglitazone caused necrosis. Since preincubation with the ROS scavengers manganese (III) tetrakis (4-benzoic acid) porphyrin and vitamin c significantly inhibited ciglitazone- and partially troglitazone-mediated cell death we suggest that ROS contribute to cytotoxic effects. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Using the pharmacological inhibitors for complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death whereas inhibition of complex I provoked only marginally apoptosis after 4 h treatment. Therefore inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone in contrast to troglitazone is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure thiazolidinediones differently affect cell death which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.

Key words: PPARs, Apoptosis, Mitochondrial toxins, Oxidative stress/antioxidants, Mechanisms of cell killing/apoptosis

This article has been cited by other articles:

				P. L. K. Lim, J. Liu, M. L. Go, and U. A. Boelsterli The Mitochondrial Superoxide/Thioredoxin-2/Ask1 Signaling Pathway is Critically Involved in Troglitazone-Induced Cell Injury to Human Hepatocytes Toxicol. Sci., February 1, 2008; 101(2): 341 - 349. [Abstract] [Full Text] [PDF]