Reduction of expression of the multidrug resistance protein (MRP)1 in glioma cells by antisense phosphorothioate oligonucleotides.
The tumor cells' acquisition of resistance to multiple drugs due to overexpression of the multidrug resistance protein (MPRP)1 gene is one of major obstacles in cancer chemotherapy. We have attempted to reverse the multidrug resistance (MDR) phenotype by treating etoposide resistant glioma cell lines (T98G-VP and Gli36-VP) with RP1 antisense oligonucleotides. 20-mer phosphorothioate oligodeoxynucleotide (0.3 microM), complementary to the coding region in the MRP cDNA sequence, could significantly inhibit the growth of multidrug resistant cell lines, T98G-VP and Gli36-VP, cultured in etoposide containing medium. No such effect was observed for the parental T98G and Gli36 cell lines. Further investigations by the reverse transcription-polymerase chain reaction and immunoblotting revealed that antisense oligomer could result in a reduction in the level of MRP1 mRNA, probably through hindering MRP1 gene transcription. This study demonstrates that the antisense oligonucleotides can increase the sensitivity of the tumor cells to the anticancer drug by decreasing the expression of the MRP gene. This strategy may be applicable to cure cancer patients with MRP mediated MDR phenotype.
Department of Neurological Surgery, Kagawa University School of Medicine, Kagawa, Japan.
Yoshihito
Y
Matsumoto
Keisuke
K
Miyake
Katsuzou
K
Kunishio
Takashi
T
Tamiya
Nagao
N
Seigo
D001483:Base Sequence; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics
D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C421109:multidrug resistance-associated protein 1