Restoration of chemosensitivity in cancer cells with MDR phenotype by deoxyribozyme, compared with ribozyme

• Published in: Experimental and molecular pathology Vol. 94; no. 3; pp. 481 - 485
• Main Authors: Xing, Ai-Yan, Shi, Duan-bo, Liu, Wei, Chen, Xu, Sun, Yan-Lin, Wang, Xiao, Zhang, Jian-ping, Gao, Peng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.06.2013
• Subjects: Antineoplastic Agents - pharmacology; ASODN; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Cell Line, Tumor; Cell Survival - genetics; DNA, Catalytic - genetics; DNA, Catalytic - metabolism; Doxorubicin - pharmacology; Drug Resistance, Multiple - genetics; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia - genetics; Leukemia - therapy; Multidrug resistance; Oligonucleotides, Antisense - genetics; P-glycoprotein; Phosphorothioate Oligonucleotides; Suppress; Transfection; Vinblastine - pharmacology; P-glycoprotein; Transfection; Suppress; ASODN; Multidrug resistance
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2013.03.004

One of the main mechanisms for multidrug resistance (MDR) involves multidrug resistance gene 1 (MDR1) which encodes P-glycoprotein (Pgp). Pgp acts as a drug efflux pump and exports chemotherapeutic agents from cancer cells. Specific inhibition of Pgp expression by gene therapy is considered a well-respective strategy having less innate toxicities. At present, the investigation of DRz in reversal MDR is scarce. In the study, phosphorothioate DRz that targets to the translation initiation codon AUG was synthesized and transfected into breast cancer cells and leukemia cells with MDR phenotype. ASODN (antisense oligonucleotide) and ribozyme targets to the same region were also synthesized for comparison analysis. Alterations in MDR1 mRNA and Pgp were determined by RT-PCR, Northern blot, flow cytometry and Rh123 retention tests. Chemosensitivity of the treated cells was determined by MTT assay. The results showed that DRz could significantly suppress expression of MDR1 mRNA and inhibit synthesis of Pgp. The efflux activity of Pgp was inhibited accordingly. Chemosensitivity assay showed that a 21-fold reduction in drug resistance for Adriamycin and a 45-fold reduction in drug resistance for Vinblastine were found in the treated cells 36h after transfection. These data suggest that DRz targeted to the translation initiation codon AUG can reverse MDR phenotype in cancer cells and restore their chemosensitivity. Moreover, the reversal efficiency of DRz is better than that of ribozyme and ASODN targets to the same region of MDR1 mRNA. •At present, the investigation of DRz to reverse MDR is scare.•The study provides the evidence of DRz to restore chemosensitivity in cancer cells.•The reversal efficiency of DRz is better than ribozyme targeted to the same mRNA.