title: Sequence-dependent synergistic inhibition of human glioma cell lines by combined temozolomide and miR-21 inhibitor gene therapy.
abstract: Down-regulation of microRNA-21 (miR-21) can induce cell apoptosis and reverse drug resistance in cancer treatments. In this study, we explored the most effective schedule of the miR-21 inhibitor (miR-21i) and Temozolomide (TMZ) combined treatment in human glioma cells. Three tumor cell lines, U251 phosphatase and tensin homologue (PTEN) mutant, LN229 (PTEN wild-type), and U87 (PTEN loss of function), were subjected to evaluate the antitumor effects of deigned treatments (a predose of miR-21i for 4/8 h and then a subsequent TMZ treatment, a predose of TMZ for 4/8 h and then a subsequent miR-21i treatment, or a concomitant treatment) in vitro. A synergistic antiproliferative and proapoptotic activity was only obtained in U251 and U87 cells when a predose was administered for 4 h before the treatment of the other therapeutic agent, while the best antitumor effect in LN229 cells was achieved by using the concomitant treatment. Our data indicate that the effect of sequence and timing of administration is dependent on the PTEN status of cell lines. The best suppression effect was achieved by a maximal inhibition of STAT3 and phosphorylated STAT3, in PTEN loss of function cells. Our results reveal that both the sequence and the timing of administration are crucial in glioma combination therapy.
authors.affiliation: School of Materials Science & Engineering, Tianjin University, Tianjin 300072, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Qian
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Shi
authors.forename: Lixia
authors.initials: L
authors.lastname: Long
authors.forename: Peiyu
authors.initials: P
authors.lastname: Pu
authors.forename: Jing
authors.initials: J
authors.lastname: Sheng
authors.forename: Xubo
authors.initials: X
authors.lastname: Yuan
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050091:Dendrimers / Q000008:administration & dosage; D004357:Drug Synergism; D015316:Genetic Therapy / Q000379:methods; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D053758:Nanoparticles / Q000008:administration & dosage; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D050091:Dendrimers; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C104700:PAMAM Starburst; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003606:Dacarbazine; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077204:Temozolomide