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.

Targeting strategies on miRNA-21 and PDCD4 for glioblastoma

“…88 Using the miR-21 inhibitor (miR-21i) together with TMZ to treat human glioma cell lines, a synergistic antiproliferative and proapoptotic activity was obtained in U251 (PTEN mutated) and U87 (loss of PTEN function) cells (a predose of miR-21 for 48 h then TMZ treatment), but the best antitumor effect was achieved in LN229 cells (wild-type PTEN). 89 Acquired TMZ-resistance due to chronic TMZ exposure resulted in elevated miR-21 expression, while concomitant treatment with miR-21 inhibitor and TMZ led to a significantly higher apoptotic rate than TMZ treatment alone. 90 Taken together, the effect of combined treatment of miR-21 inhibitor with other therapeutic agent is dependent on the PTEN status, and the best suppression effect was achieved in PTEN loss of function U87 cells by a maximal inhibition of STAT3 and phosphorylated STAT3.…”

New Approach to Develop Ultra-High Inhibitory Drug Using the Power Function of the Stoichiometry of the Targeted Nanomachine or Biocomplex

“…In most cases of the sequential, cooperative and precessive reaction, inactivation of any one, not necessary all, of the subunits will result in inhibition of its function, thus K = 1. Drug synergism was utilized in multitarget drug therapy; in short, a drug combination can simultaneously act on multiple targets in disease networks to produce a synergistic effect [50,81]. However, our design reported here is unique from the conventional synergistic approach.…”

MiR-21 confers resistance against CVB3-induced myocarditis by inhibiting PDCD4-mediated apoptosis

“…As illustrated by the immunohistochemistry results, the number of PDCD4-positive myocardiocytes was signi cantly reduced in mice receiving pMDH-miR-21, indicating that miR-21 e ciently inhibited its target PDCD4 expression and decreased the subsequent myocardial apoptosis. Other apoptosis-associated targets of miR-21, such as tumor suppressor phosphatase and tensin homolog (PTEN) [47] and Fas ligand and metalloproteinase inhibitor 3 (TIMP3) [48], may also participate in CVB3-induced myocarditis, and further studies need to be conducted for validation.…”