STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non–Small Cell Lung Cancer

Abstract

Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 μmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T ( < 0.007) and H1975 models ( < 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC. .

Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy

“…Nevertheless, the studies on the TFD strategy have an indication of the limitations of this approach for being used in the clinic. Currently, several structural modifications for improved stability (i.e., phosphorothioated modification, locked nucleic acids substitutions, Ribbon‐type structure) and novel methods for efficient transfer into the cells (i.e., polymer d , l ‐lactide‐co‐glycolide and cell‐penetrating peptide) are considered to make ODNs as a candidate for differentiation therapy in clinic (Njatcha et al, ; Osako, Nakagami, & Morishita, ). Furthermore, decreasing the decoy toxicity by means of the circularized cyclic structure is proposed to ensure its safety.…”

“…Data were normalized to GAPDH reference gene messenger RNA expression levels and displayed as the mean ± standard deviation. p < .05(*), p < .001(***), and p < .0001(****) versus the control group (one-way analysis of variance) F I G U R E 8 Overview of suppressing the metastatic properties of the breast cancer cells using a signal transducer and activator of transcription 3 (STAT3) decoy oligodeoxynucleotides (ODN) structural modifications for improved stability (i.e., phosphorothioated modification, locked nucleic acids substitutions, Ribbontype structure) and novel methods for efficient transfer into the cells (i.e., polymer D,L-lactide-co-glycolide and cell-penetrating peptide) are considered to make ODNs as a candidate for differentiation therapy in clinic (Njatcha et al, 2018;Osako, Nakagami, & Morishita, 2012). Furthermore, decreasing the decoy toxicity by means of the circularized cyclic structure is proposed to ensure its safety.…”

Targeting STAT3 in Cancer Immunotherapy

“…Oligonucleotides represent a new treatment strategy for ‘undruggable’ cancer targets such as STAT3. STAT3-binding decoy oligodeoxynucleotides, can sequester STAT3 and thus decrease its binding to cognate DNA sites within target genes [ 133 ]. Antisense oligonucleotides (ASOs) are designed to block STAT3 activity by targeting STAT3 mRNA.…”

Evaluation of STAT3 decoy oligodeoxynucleotides' synergistic effects on radiation and/or chemotherapy in metastatic breast cancer cell line

“…Among several strategies, antisense therapy by oligodeoxynucleotides decoys (Bigdelou et al, 2019; Johari et al, 2019), which impairs interaction between transcription factors and related binding site in theirs correspond genes promoter in the genome, has been used successfully for blocking of the activities of STAT3 protein (Leong et al, 2003; Njatcha et al, 2018). This study aimed to evaluate the efficiency of a combinational therapy strategy of 22‐bp double‐stranded STAT3 decoy ODNs treatment with XI, MTX, and XI‐MTX exposure in highly metastatic breast cancer MDA‐MB‐231 cells through an in vitro analysis.…”