Sensitization and apoptosis augmentation of K562/ADM cells by anti-multidrug resistance gene peptide nucleic acid and antisense oligodeoxyribonucleotide.
OBJECTIVE
To investigate the reversal effect and apoptosis enhancement of peptide nucleic acid (PNA) and antisense oligodeoxyribonucleotide (ASODN) targeted to multidrug resistance gene (mdr1) on human multidrug resistant leukemia K562/ADM cells.


METHODS
A 15-mer PNA and the same sequence of ASODN, complementary to the 5' end of the AUG initiator codon-containing region of mdr1 messenger RNA (MDR1-PNA, MDR1-ASODN), were designed and synthesized. Proliferation and sensitivity to adriamycin of K562/ADM cells treated with MDR1-PNA- and MDR1-ASODN were analyzed with a MTT colorimetric assay. Apoptotic morphologies, P-glycoprotein (P-gp) expression, intracellular adriamycin accumulation, and cell cycle were measured.


RESULTS
MDR1-PNA 1 to 10 micromol/L and MDR1-ASODN 2 to 20 micromol/L alone had no inhibitory effects on the proliferation of K562/ADM cells, but significantly inhibited the growth of K562/ADM cells cultured in adriamycin-containing medium. After treatment with MDR1-PNA and MDR1-ASODN, intracellular adriamycin accumulation in K562/ADM cells increased greatly and P-gp synthesis was strikingly reduced. The resistance to adriamycin of the drug-resistant cells was partly reversed and the cells were induced to apoptosis by adriamycin. The reversal efficacy of MDR1-PNA was 3.1-fold higher than that of the same sequence of MDR-ASODN, but neither MDR1-PNA nor MDR1-ASODN could completely block the mdr1/P-gp expression.


CONCLUSIONS
Sequence-special PNA targeted to mdr1 gene more effectively than the same sequence of MDR1-ASODN inhibited the expression of P-glycoprotein to overcome the drug-resistance.
Wei
Hu-Lai
HL
Laboratory Center for Medical Science, Lanzhou Medical College, Lanzhou 730000, China. weihl@public.lz.gs.cn.
Wu
Yong-Jie
YJ
Jing
Tao
T
Bai
De-Cheng
DC
Ma
Lan-Fang
LF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020014:K562 Cells; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D020135:Peptide Nucleic Acids / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D020135:Peptide Nucleic Acids; D004317:Doxorubicin