Antisense Oligonucleotides of XIAP Reverse Resistance to Phenytoin and Carbamazepine in K562 Cells and Rats of Intractable Epilepsy

Abstract

There is accumulating evidence that apoptosis plays a key role in genesis of epilepsy, but the relationship between apoptosis and drug resistance in medically intractable epilepsy is not clear. The effect of XIAP antisense oligonucleotides on drug resistance in K562/Dox cells and rats of intractable epilepsy was investigated. The multidrug resistance cell line K562/Dox was established, and the expression of XIAP in K562/Dox cells and normal K562 cells was observed. After XIAP antisense oligonucleotides was transiently transfected into K562/Dox cells, mitochondrial membrane potential was assessed using JC-1. At the same time, antiepileptic drugs resistant in K562/Dox cells was measured by MTT. In addition, the model of intractable epilepsy was established by kindling of amygdale in rats. After XIAP antisense oligonucleotides was applied to PHT-CBZ resistant rats by lateral ventricle, after discharge threshold(ADT) and after discharge duration(ADD) was observed. The results showed that the expression of XIAP was significantly increased in K562/Dox cells compared with K562 cells. After XIAP antisense oligonucleotides was transiently transfected into K562/Dox cells, the expression of XIAP was regulated down, and mitochondrial membrane potential of K562/Dox cells was decreased. Moreover, XIAP down-regulation could increase the sensitivity of K562/Dox cells to antiepileptic drugs. The level of IC50 was decreased significantly in K562/Dox cells, and the reversal index were 1.76 and 1.73, respectively. Furthermore, animal studies found that, compared with control group, ADT was significantly higher (P 0.05) and ADD shortened in PHT-CBZ resistant rats after XIAP antisense oligonucleotides was applied. It is obvious that the expression of XIAP was significantly increased in drug resistant K562/Dox cells. Down-regulation of XIAP could reverse the drug-resistance of K562/Dox cells, and improve the electrobiological activity in PHT-CBZ resistant rats. These findings indicate that XIAP is involved in multidrug resistance in medically intractable epilepsy.

Keywords

Identifiers

DOI

10.3724/sp.j.1206.2009.00709

Journal

PROGRESS IN BIOCHEMISTRY AND BIOPHYSICS

Year

2010