Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice
Xulong Zhang1, Jian Zhang, Lihua Wang
1Institute of Immunopharmacology & Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. zhxlwl@yahoo.com.cn
Background:
Signal transducer and activator of transcription 3 (STAT3) is usually constitutively activated in a variety of malignancies. Therefore, STAT3 may be a promising target for treatment of tumor cells. To explore the possibility of a double-stranded decoy oligodeoxynucleotide (ODN) targeted blocking STAT3 over-activated tumor cells, we, here, evaluate the efficacy of STAT3 decoy ODN on human lung cancer cells in vitro and in vivo.
Methods:
A STAT3 decoy ODN was transfected into A549 lung cancer cell line in vitro by using lipofectamine. The flow cytometry and fluorescent microscopy were used to detect the transfection efficiency and the sub-cellular localization of STAT3 decoy ODN in A549 cells. Cell proliferation was determined by counting cell numbers and [3H]-thymidine uptake. Cell apoptosis was examined with Annexin V and propidum iodide by flow cytometry. The expression levels of STAT3 target genes were identified by RT-PCR and immunoblot. For in vivo experiment, A549 lung carcinoma-nude mice xenograft was used as a model to examine the effect of the STAT3 decoy by intratumoral injection. At the end of treatment, TUNEL and immunohistochemistry were used to examine the apoptosis and the expression levels of bcl-xl and cyclin D1 in tumor tissues.
Results:
STAT3 decoy ODN was effectively transfected into A549 lung cancer cells and mainly located in nucleus. STAT3-decoy ODN significantly induced apoptosis and reduced [3H]-thymidine incorporation of A549 cells as well as down-regulated STAT3-target genes in vitro. STAT3 decoy ODN also dramatically inhibited the lung tumor growth in xenografted nude mice and decreased gene expression of bcl-xl and cyclin D1.
Conclusion:
STAT3 decoy ODN significantly suppressed lung cancer cells in vitro and in vivo, indicating that STAT3 decoy ODN may be a potential therapeutic approach for treatment of lung cancer.
Insights
Signal transducer and activator of transcription 3 (STAT3) decoy oligodeoxynucleotides (ODNs) effectively suppressed lung cancer cells in vitro and in vivo. This STAT3 decoy ODN demonstrates potential as a novel therapeutic strategy for lung cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Oligonucleotide Therapeutics
Background:
- Constitutive activation of Signal transducer and activator of transcription 3 (STAT3) is prevalent in various malignancies.
- STAT3 represents a promising therapeutic target for cancer treatment.
- Investigating STAT3 decoy oligodeoxynucleotides (ODNs) for targeted blocking of over-activated tumor cells.
Purpose of the Study:
- To evaluate the efficacy of STAT3 decoy ODN in human lung cancer cells.
- To assess the in vitro and in vivo therapeutic potential of STAT3 decoy ODN.
Main Methods:
- Transfection of STAT3 decoy ODN into A549 lung cancer cells using lipofectamine.
- Assessment of transfection efficiency and cellular localization via flow cytometry and fluorescent microscopy.
- Evaluation of cell proliferation, apoptosis, and STAT3 target gene expression (in vitro).
- Intratumoral injection of STAT3 decoy ODN in a human lung carcinoma-nude mice xenograft model (in vivo).
- Analysis of tumor apoptosis and gene expression (bcl-xl, cyclin D1) using TUNEL and immunohistochemistry.
Main Results:
- Effective transfection and nuclear localization of STAT3 decoy ODN in A549 cells.
- Significant induction of apoptosis and reduction in proliferation ([3H]-thymidine incorporation) in vitro.
- Down-regulation of STAT3 target genes observed in vitro.
- Dramatic inhibition of lung tumor growth in vivo.
- Decreased expression of bcl-xl and cyclin D1 in tumor tissues.
Conclusions:
- STAT3 decoy ODN significantly suppresses lung cancer cell proliferation and induces apoptosis.
- STAT3 decoy ODN demonstrates efficacy both in vitro and in vivo.
- STAT3 decoy ODN represents a potential therapeutic approach for lung cancer treatment.
