title: Inhibition of mdr1 by G-quadruplex oligonucleotides and reversal of paclitaxel resistance in human ovarian cancer cells.
abstract: The expression of ATP-dependent efflux pump P-glycoprotein (P-gp) in cancer cells generally results in multidrug resistance (MDR) to chemotherapeutic drugs, which is the main cause of chemotherapy failure in cancer treatment. The intracellular drug levels could be increased by some MDR reversal agents that inhibited the drug efflux activity of P-gp. The synthesized DNA nucleic acids of G-quadruplex represent a novel and unique class of anti-cancer agents. While there was no report on the roles of DNA G-quadruplex oligonucleotides (GQ-ODNs) in the MDR reversal, the present study was performed to investigate the ability of synthesized GQ-ODNs to reverse P-gp-mediated MDR and its mechanism in paclitaxel (PTX)-resistant SKOV3 (SKOV3/PTX) cells and their sensitive cell lines SKOV3. The ability of GQ-ODNs to reverse drug resistance was evaluated by MTS assay. The results showed that GQ-ODNs can reverse PTX resistance effectively. The potential of GQ-ODNs as reversal agents was evaluated with the nude mice tumor xenograft model and showed that the co-administration of the GQ-ODNs and PTX had better effects and was also more evident than treatment with only PTX. The P-gp expression was assessed by the Western blot; it showed that SKOV3/PTX cells showed highly expressed P-gp protein, while their sensitive cells scarcely showed P-gp. The presence of GQ-ODNs efficiently decreased the P-gp expression, showing that GQ-ODNs could reverse P-gp-mediated MDR by decreasing the expression of P-gp. This study indicated that GQ-ODNs could effectively reverse P-gp-mediated PTX resistance by inhibiting the expression of P-gp and by the co-administration of GQ-ODNs and PTX that could increase the apoptosis of SKOV3/PTX cells. Thus, the synthesized GQ-ODNs may be a potential inhibitor to overcome drug resistance.
authors: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China, wangbiao@mail.cmu.edu.cn.
authors: Biao
authors: B
authors: Wang
authors: Shuo
authors: S
authors: Li
authors: Xin
authors: X
authors: Meng
authors: Hong
authors: H
authors: Shang
authors: Yifu
authors: Y
authors: Guan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D054856:G-Quadruplexes; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D017239:Paclitaxel